Department of Health and Human Services
Part 1. Overview Information

 

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute on Aging (NIA)

Funding Opportunity Title

Alzheimer Centers for Discovery of New Medicines (U54 Clinical Trial Not Allowed)

Activity Code

U54 Specialized Center- Cooperative Agreements

Announcement Type

New

Related Notices
Funding Opportunity Announcement (FOA) Number

RFA-AG-19-010  

Companion Funding Opportunity

None

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.866  

Funding Opportunity Purpose

This Funding Opportunity Announcement (FOA) invites U54 Cooperative Agreement applications aiming to establish multi-component Alzheimer Centers for the Discovery of New Medicines. The overarching purpose of this Centers program is to improve, diversify and reinvigorate the Alzheimer's disease (AD) drug development pipeline by accelerating the characterization and experimental validation of next generation therapeutic targets and integrating the targets into drug discovery campaigns. In addition, this program aims to de-risk potential therapeutics to the point that industry will invest in them, accelerating the delivery of new drugs to AD patients. To this end, the funded Centers will 1) design, develop and disseminate tools that support target enabling packages (TEPs) for the experimental validation of novel, next generation therapeutic targets, including those emanating from the NIA-funded, target discovery programs such as AMP-AD, and 2) initiate early stage drug discovery campaigns against the enabled targets.  

Key Dates

 

Posted Date

August 2, 2018

Open Date (Earliest Submission Date)

January 1, 2019

Letter of Intent Due Date(s)

January 1, 2019

Application Due Date(s)

February 1, 2019, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on this date.

No late applications will be accepted for this Funding Opportunity Announcement.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

June 2019

Advisory Council Review

August 2019

Earliest Start Date

September 2019

Expiration Date

February 2, 2019

Due Dates for E.O. 12372

Not Applicable

** ELECTRONIC APPLICATION SUBMISSION REQUIRED**

NIH's new Application Submission System & Interface for Submission Tracking (ASSIST) is available for the electronic preparation and submission of multi-project applications through Grants.gov to NIH. Applications to this FOA must be submitted electronically using ASSIST or an institutional system-to-system solution; paper applications will not be accepted.

Required Application Instructions

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.


There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.

  3. Table of Contents

    Part 1. Overview Information
    Part 2. Full Text of the Announcement

    Section I. Funding Opportunity Description
    Section II. Award Information
    Section III. Eligibility Information
    Section IV. Application and Submission Information
    Section V. Application Review Information
    Section VI. Award Administration Information
    Section VII. Agency Contacts
    Section VIII. Other Information


    Part 2. Full Text of Announcement
    Section I. Funding Opportunity Description
    Purpose

    This Funding Opportunity Announcement (FOA) invites applications to establish multi-component Alzheimer Centers for Discovery of New Medicines. The overarching objective of this Centers program is to improve, diversify and reinvigorate the Alzheimer's disease (AD) drug development pipeline by accelerating the characterization and experimental validation of next generation therapeutic targets and integrating the targets into drug discovery campaigns. More specifically, each funded Center will 1) design, develop and disseminate tools that support target enabling packages (TEPs) for the experimental validation of novel, next generation therapeutic targets, including those emanating from the NIA-funded target discovery programs such as AMP-AD/AMP-AD Wall of Targets, and 2) initiate early stage drug discovery campaigns against the enabled targets. To achieve these goals, it is expected that each Center will be staffed by a multi-disciplinary team of scientists with combined expertise in data science, computational biology, network biology, disease biology, structural genomics, biostatistics, assay development, medicinal chemistry, pharmacology, and clinical science. Central to this initiative is the open-access, rapid dissemination of data, methods, and computational and experimental tools generated by the Centers to all qualified researchers for their use in advancing AD drug discovery and AD disease biology.

    Background

    Alzheimer's disease (AD) is the most common cause of dementia in elderly persons and is among the greatest healthcare challenges of the 21st century. The disease currently affects an estimated 5.5 million in the United States; by 2050 this number could rise as high as 14 million. Delaying symptom onset by five years could reduce disease prevalence by as much as 50%; this would significantly reduce the human burden and health care costs associated with the disease. Unfortunately, the clinically available therapies fall short of this requirement and provide only limited and temporary relief of symptoms. Therefore, to avert this large and escalating public health crisis, new therapies that effectively prevent, slow the progression or improve the symptoms of AD are urgently needed.  Unfortunately, despite more than two decades of massive investment and research, not one drug purported to prevent, slow, or cure AD has successfully completed the FDA-required clinical testing process. In fact, over this timespan there has been an extremely high attrition rate of AD treatments in Phase II and Phase III, with more than half failing due to issues of efficacy.

    Many factors have contributed to the lack of progress in developing effective AD therapies, including the strong possibility that AD drug candidates have failed in the clinic because their development has been based on a very narrow understanding of the disease that is centered on the amyloid hypothesis. In contrast to this conventional wisdom, growing amounts of new data suggest that clinical AD is a highly heterogeneous, multimodal and multicomponent disease, caused by manifold genetic and environmental factors acting to perturb molecular networks across multiple interrelated biological pathways. This realization, coupled with the failure of numerous anti-amyloid drugs, has raised a degree of skepticism on the current amyloid-based model of AD and has highlighted the need for alternative therapeutic approaches that require the identification of next generation, novel AD drug targets. Therefore, to improve, reinvigorate and diversify the AD drug development pipeline, next generation targets must be evaluated, prioritized, and advanced into drug discovery campaigns.

    In 2013 the NIA launched the AMP-AD Target Discovery initiative to facilitate the discovery and preclinical validation of the next-generation AD drug targets. AMP-AD is a large-scale, open-science consortium and, as such, all generated data and analysis are deposited into a common data sharing platform—the AMP-AD Wall of Targets —for rapid and broad dissemination into the public domain. The overarching aims of AMP-AD include: building a predictive, multiscale model of AD that better represents disease heterogeneity; identifying potential therapeutic targets; and gaining a systems-level understanding of the gene, protein, and metabolic networks within which the targets operate. To accomplish these goals AMP-AD has taken a systems and network biology approach that integrates multiple outcome measures (i.e., genetic, neuropathological, clinical, neuroimaging, fluid biomarker, and environmental), together with state-of-the art, multi-level "-omics" of normal and AD human brain, cell and animal model bio-samples. Taken together, these data have been used to generate experimental gene/protein interaction networks that, in turn, have been used to build computational models of AD. Through this process AMP-AD investigators have identified a series of novel molecular networks, and their key regulators or network drivers, that are associated with different, stage-specific AD endophenotypes. Given that the network drivers represent genes/proteins, it is highly plausible that some of these nodal points are potential drug targets. Based on these suppositions, an analysis, across the AMP-AD consortium, of molecular networks and their key drivers has led to the identification of more than 30 candidate drug targets.

    Target identification is a critical first step in the drug discovery pipeline; however, before integration into a drug discovery campaign a candidate target must undergo an evaluation and prioritization process. This typically includes an assessment across a common set of selection criteria such as genetic evidence, druggability, assay-ability, availability of crystal structure, and availability of known ligands, followed by preclinical validation aimed at understanding target biology and demonstrating a functional role of the target in a disease phenotype. The robust validation of candidate drug targets requires the integral use of a diverse set of approaches, tools, reagents, and information; these include computational approaches to assist in target prioritization, and tools/reagents for experimental target validation. The challenge to fully evaluating, prioritizing and advancing candidate targets into drug discovery is that many of the targets are not well studied, and for most there are no tools or reagents for target validation or drug discovery. Therefore, to capitalize on the innovations and discoveries of AMP-AD, and other target discovery programs, it is imperative to design and develop tools, methods and reagents that will enable next generation AD drug targets for entry into drug discovery. The open dissemination of these experimental tools, methods and reagents, to all qualified scientists, will ensure collaborative, transparent, and reproducible research, and eventually de-risk potential therapeutics to the point that industry will invest in them, accelerating the delivery of new drugs to AD patients.

    Research Objectives and Scope

    The overarching objective of this initiative is to create Alzheimer Translational Centers focused on improving, diversifying and reinvigorating the AD drug development pipeline. Further, this program aims to de-risk potential therapeutics to the point that industry will invest in them, thereby accelerating the delivery of new drugs to AD patients. To this end, the new Centers will bring together technology and expertise needed to design and develop tools and methods that enable the characterization and experimental validation of candidate drug targets, including those emanating from the AMP-AD, and initiate drug discovery campaigns against these targets. In addition, this initiative will promote the open-access, rapid dissemination of all data, methods, and tools generated by the Centers to all qualified researchers, for their use in advancing AD drug discovery and/or elucidating disease biology. To achieve these goals the Centers will need to bring together multi-disciplinary teams of experts in computational biology, network biology, disease biology, biochemistry, biophysics, structural biology, biostatistics, assay development, medicinal chemistry, pharmacology, and clinical science.

    Specifically, this FOA will provide support for:

    1) developing computational and bioinformatic tools and methods to assess multicomponent data emanating from the AMP-AD/AMP-AD Wall of Targets and other NIA-funded target discovery programs to assist in prioritizing drug targets for validation and drug discovery;

    2) designing and developing research reagents, tools and methods that support target enabling packages (TEPs) for prioritized drug targets, to be used for the validation and integration of drug targets into drug discovery campaigns;

    3) developing and optimizing assay systems for target validation and early stage drug discovery;

    4) launching robust early drug discovery campaigns against prioritized/enabled candidate drug targets;

    5) delivering lead compounds suitable for further drug development and for efficacy testing in AD animal models (e.g., through the NIA-funded MODEL-AD program); and

    6) establishing a publicly available data sharing platform housing all data generated by the Center.

    In addition, this initiative will promote the rapid dissemination of all tools and methods generated by the Center to all qualified researchers for their use in drug discovery and advancing the understanding of disease biology.

    Specific areas of research interest include but are not limited to:

    • Developing computational tools and bioinformatic methods that assess evidence on candidate targets emanating from the AMP-AD/AMP-AD Wall of Targets and other target identification programs to support prioritization of candidate drug targets for experimental validation and drug discovery.
    • Developing reagents, tools and methods that support Target Enabling Packages (TEPs) for characterization and validation candidate targets. A typical TEP tool kit will include the following:
    • purified target proteins to assess biochemical and biophysical properties
    • methods to determine 3-D structures using the latest technology i.e., cryo-EM
    • antibodies and/or nanobodies against target proteins
    • small molecule molecular probes that modulate the activity and function of target proteins
    • siRNA and gene editing tools (e.g., CRISPR/Cas9) for manipulation of target protein genes
    • in silico tools and methods for virtual ligand screening and profiling
    • suite of assay platforms to assess ligand binding, enzyme activity, biophysical properties, including High Throughput Screen (HTS) assays for molecular probe discovery and cell-based assays to measure target engagement and assess biological target activity and downstream consequences of target modulation
    • Launching early drug discovery campaigns for enabled candidate targets. A typical drug discovery campaign will include the following:
    • chemical libraries for robotic and in silico screening
    • cheminformatics tools and methods
    • a suite of screening platforms to identify molecular probes, "hit" compounds, including robotic and in silico HTS and phenotypic screens with emphasis on human iPSCs
    • iterative, hit-to-lead medicinal chemistry for optimization of drug-like properties, potency, target selectivity, and pharmacological properties
    • tools and methods that enable in silico pharmacology
    • selectivity and counter-screening assays to address potential activity at related targets and other undesirable activities or artifacts
    • assays and tools for pharmacological characterization including early pharmacokinetic and ADME/T profiling lead candidates
    • assays for early toxicology profiling of lead candidates
    • cell-based and animal models to assess in vivo efficacy and target engagement of lead candidates
    • Developing strategies and web-based infrastructure for rapid, open-access dissemination of data and methodology and for rapid distribution of all tools and methods for their use in AD therapy development.
    Overall Organization of the Center

    The Center should have the following structure:

    • The Administrative and Data Management Core will serve as the focus for the synergistic activities of the Center. Through the Steering Committee, it will be responsible for managing, coordinating, and supervising the entire range of Center activities, including monitoring progress and ensuring that the overall project management plan is effectively implemented and that yearly milestones are achieved within proposed timelines. In addition, the Core will be responsible for: maintaining an internal and an outward facing, publicly available data platform housing data generated by the Center; oversight for open-access sharing and distribution of tools, assays, models, methods and data to all qualified scientists from the academic and biopharma communities; and organizing an annual meeting held to facilitate communication and collaboration among Center scientists, members of the External Advisory Board (EAB), and scientists from other NIA-funded Centers.
    • The Bioinformatics and Computational Biology Core will develop and deploy analytical tools and methods that enable the identification and prioritization of candidate drug targets for experimental validation and entry into drug discovery. For this purpose, the Core will use both standard and innovative biostatistics, bioinformatics and computational biology approaches to analyze and interpret high-dimensional data emanating from the AMP-AD and deposited on the AMP-AD Wall of Targets platform and from other external databases (i.e., ADSP, ADGC, ADNI, MODEL-AD).
    • The Structural Biology Core will develop high-quality reagents, tools and methods that support Target Enabling Packages (TEPs) for the experimental characterization, validation, and eventual translation of candidate targets into drug discovery campaigns. The Core will be responsible for cloning and sub-cloning candidate target genes; protein production; biochemical and biophysical characterization of candidate target proteins; determination of 3-D protein structures using cutting-edge technologies (i.e., cryo-EM); in silico approaches that inform target validation; design and production of recombinant antibodies; and design of siRNA/shRNA and gene editing tools for target gene manipulations. This Core, in collaboration with the Assay Development Core, will develop biochemical assays suitable for functional characterization and cell-based assays for target modulation, including phenotypic screens with emphasis on human iPSCs.
    • The Assay Development and High Throughput Screening Core will develop innovative assay and screening methods to enable a wide range of the Center's activities, including characterization and experimental validation of candidate targets and drug discovery. Specific capabilities should include assay design, optimization, validation, miniaturization and transfer. The Core will develop: high throughput screens (HTS); biochemical and cell-based assays for target modulation including phenotypic screens with emphasis on human iPSCs; HTS screening platforms to identify "hit" compounds for molecular probe and small molecule drugs; and screens for early cytotoxicity profiling of "hits" and lead candidates. In addition, the Core will provide support for interpretation and analysis of data derived from these assays.
    • The Medicinal Chemistry and Chemical Biology Core will provide molecular probe development and drug discovery services to Center. These will include: custom library development, synthesis and curation; in silico HTS screening of compounds libraries; advanced cheminformatics analysis on primary robotic and in silico high-throughput HTS hit data; computational resources for managing chemical structures and data; scale-up synthesis for hit validation and medicinal chemistry optimization; computational docking studies and analyses; molecular probe synthesis for target validation; chemical biology approaches to selectively modulate the activity of candidate drug targets; synthetic medicinal chemistry for hit-to-lead optimization; structure-activity relationship (SAR) analysis; fragment-based drug discovery; analysis of drug-like and physical-chemical properties (i.e. drug stability and solubility); support for drug structural determination (i.e., NMR, MS); and exploratory pharmacology (i.e., early PK and ADME/T profiling).
    • The Center Steering Committee will serve as the operational governing board. The Steering Committee should include the PD(s)/PI(s), Unit leads, the NIH Project Scientist (voting), and external scientist(s) (if required). Among other functions, the Steering Committee will have primary responsibility for finalizing standard procedures and protocols; holding regular webinars/teleconferences; developing a prioritized portfolio of therapeutic targets for validation and drug discovery; deciding which  drug target projects will be initiated by the Center; and evaluation of lead candidates generated by the Center and their prioritization for entry into animal efficacy studies (MODEL-AD) and entry into  other NIA/NIH drug development programs.
    • The External Advisory Board should be organized from non-conflicted experts outside of the Center to guide the Center leadership in assessing the Center's progress in achieving the yearly milestones, assessing new scientific opportunities as they are presented and evaluating the effectiveness of interaction among Cores and Center participants. The external advisory board will advise the steering committee on different aspects of the Center's function, including prioritization of projects; changes in direction or approach; sharing of tools, methods and data; and problem identification and resolution.
    Milestones

    Milestone-driven research is used to ensure research is focused on a well-defined goal and achieving that goal with greatest efficiency. As translational research is inherently high risk, the use of milestones provides clear indicators of a project's continued success or emergent difficulties. The milestones must provide objective and quantitative success criteria which are recognizable as appropriate endpoints for a specific scientific goal and that can be used to monitor the progress made by a research project. The milestones will serve as a basis for go/no-go decision making between NIA program staff and the project research team. Prior to funding of an application, NIA Program staff will contact the applicant to discuss the proposed milestones and any modifications to the milestones as recommended by the review committee or NIA Program staff. A final set of approved milestones will be specified in the Notice of Award. Progress towards achievement of the established milestones will be evaluated by a committee composed of NIA Program Staff. NIA staff may seek advice from staff from other NIH ICs with relevant expertise, as necessary. If warranted, the milestones for future years may be revised based on data and research progress during the preceding year.

    SeeSection VIII. Other Information for award authorities and regulations.

    Section II. Award Information
    Funding Instrument

    Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA. 

    Application Types Allowed

    New

    The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

    Clinical Trial?

    Not Allowed: Only accepting applications that do not propose clinical trials

    Need help determining whether you are doing a clinical trial?

    Funds Available and Anticipated Number of Awards

    The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

    NIA intends to commit $15 million in FY 2019 to fund 1-2 awards.

    Award Budget

    Application budgets may not exceed $5.25 million in direct costs per year. Budgets must reflect the actual needs of the proposed project.

    Award Project Period

    The maximum period of support is 5 years.   

    NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

    Section III. Eligibility Information
    1. Eligible Applicants
    Eligible Organizations

    Higher Education Institutions

    • Public/State Controlled Institutions of Higher Education
    • Private Institutions of Higher Education

    The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

    o   Hispanic-serving Institutions

    o   Historically Black Colleges and Universities (HBCUs)

    o   Tribally Controlled Colleges and Universities (TCCUs)

    o   Alaska Native and Native Hawaiian Serving Institutions

    o   Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

    Nonprofits Other Than Institutions of Higher Education

    • Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
    • Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

    For-Profit Organizations

    • Small Businesses
    • For-Profit Organizations (Other than Small Businesses)

    Governments

    • State Governments
    • County Governments
    • City or Township Governments
    • Special District Governments
    • Indian/Native American Tribal Governments (Federally Recognized)
    • Indian/Native American Tribal Governments (Other than Federally Recognized)
    • Eligible Agencies of the Federal Government
    • U.S. Territory or Possession

    Other

    • Independent School Districts
    • Public Housing Authorities/Indian Housing Authorities
    • Native American Tribal Organizations (other than Federally recognized tribal governments)
    • Faith-based or Community-based Organizations
    • Regional Organizations
    Foreign Institutions

    Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
    Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

    Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

    Required Registrations

    Applicant Organizations

    Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

    • Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
    • System for Award Management (SAM) (formerly CCR) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
    • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM. 
    • eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
    • Grants.gov – Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

    Program Directors/Principal Investigators (PD(s)/PI(s))

    All PD(s)/PI(s) must have an eRA Commons account.  PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons.If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

    Eligible Individuals (Program Director/Principal Investigator)

    Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

    For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

    2. Cost Sharing

    This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

    3. Additional Information on Eligibility
    Number of Applications

    Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

    The NIH will not accept duplicate or highly overlapping applications under review at the same time.  This means that the NIH will not accept:

    • A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
    • A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
    • An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).
    Section IV. Application and Submission Information
    1. Requesting an Application Package

    A button to access the online ASSIST system is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

    Most applicants will use NIH's ASSIST system to prepare and submit applications through Grants.gov to NIH. Applications prepared and submitted using applicant systems capable of submitting electronic multi-project applications to Grants.gov will also be accepted.

    2. Content and Form of Application Submission

    It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

    For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.

    Letter of Intent

    Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

    By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

    • Descriptive title of proposed activity
    • Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
    • Names of other key personnel
    • Participating institution(s)
    • Number and title of this funding opportunity

    The letter of intent should be sent to:

    Lorenzo M. Refolo, Ph.D.

    National Institute on Aging (NIA)
    Telephone: 301-594-7576
    Fax: 301-496-1494
    Email: refolol@nia.nih.gov

    Page Limitations

    Available Component Types

    Research Strategy/Program Plan Page Limits

    Overall

    12

    Admin Core (Use for Administrative and Data Management Core)

    12

    Core (Use for Bioinformatics and Computational Biology Core; Structural Biology Core; Assay Development Core; and Medicinal Chemistry and Chemical Biology Core)

    6

    Additional page limits described in the SF424 Application Guide and the Table of Page Limits must be followed.

    Instructions for the Submission of Multi-Component Applications

    The following section supplements the instructions found in the SF424 (R&R) Application Guide, and should be used for preparing a multi-component application.

    The application should consist of the following components:

    • Overall: required; maximum 1
    • Administrative and Data Management Core: required; maximum 1
    • Bioinformatics and Computational Biology Core: required; maximum 1
    • Structural Biology Core: required; maximum 1
    • Assay Development Core: required; maximum 1
    • Medicinal Chemistry and Chemical Biology Core: required; maximum 1
    Overall Component

    When preparing your application in ASSIST, use Component Type 'Overall'.

    All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

    SF424 (R&R) Cover (Overall)

    Complete entire form.

    PHS 398 Cover Page Supplement  (Overall)

    Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

    Research & Related Other Project Information (Overall)

    Follow standard instructions.

    Other Attachments: The following should be submitted as an attachment in the form of a pdf.

    Center Organization: A diagram should be made with the organizational structure, leadership and interactions between Cores, the Steering Committee and External Advisory Board. This should reflect major decision points and demonstrate the collaborative nature of the center. Submit as a PDF entitled Center Organization.

    Project/Performance Site Location(s) (Overall)

    Enter primary site only.

    A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

    Research & Related Senior/Key Person Profile (Overall)

    Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application. To achieve the goals of this program the Center will need to bring together a multidisciplinary team with expertise in the following disciplines: bioinformatics, computational biology, structural genomics, Alzheimer's disease biology, biochemistry, assay development, medicinal chemistry, pharmacology, pre-clinical therapy development, and clinical research. Senior and key personnel should have proven expertise in the scientific discipline(s) most relevant to their role in the Center; for example, the Medicinal Chemistry and Chemical Biology Core Lead must have a proven track record in leading medicinal chemistry or drug discovery programs.

    A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

    Budget (Overall)

    The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.  

    A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

    PHS 398 Research Plan (Overall)

    Specific Aims: State concisely the goals of the Center and summarize the expected outcome(s), including the broad impact that the Center will have on Alzheimer's disease research. Specify how the Center will improve, diversify, and reinvigorate the AD drug development pipeline, and, if successful, what the impact of the Center will be on preclinical and clinical therapy development for AD. These Aims should be overarching and at a high level and distinct from the aims of the individual units. Refer to the Center Organization pdf diagram requested above.   

    Research Strategy: The Center Overview should be presented in a concise overall vision and plan for the proposed Center. Refer to the Center Organization pdf diagram requested above. This section should describe the framework for the Center, overall experimental strategy and how it will address the objectives of the program. Indicate why each component is essential for addressing the overall goal of the Center. Describe the synergy to be achieved by the Center and the multidirectional interactions between the Cores. Describe mechanisms and procedures that will promote strong collaborative interactions and "cross-fertilization" among Center investigators and participating institutions. Describe how the Center will interact with programs external to the Center such as the AMP-AD/AMP-AD Wall of Targets, other NIA-funded target discovery programs, ADNI, ADSP and, MODEL-AD. Describe how the cutting-edge science emanating from the Cores will help prioritize and enable candidate targets for drug discovery campaigns. Describe how this research will have the potential for assisting in the creation of a preclinical pipeline of therapies that can be moved forward into clinical research and practice. Describe how the Center will develop strategies and infrastructure for rapid, open science sharing of data, methods, and tools to the scientific community.

    Additional items to be addressed:

    i. Milestones and Timeline: Describe the Center's five-year critical path, with timelines and yearly milestones, from target prioritization, validation, and initiation of drug discovery campaigns to delivery of lead candidates. The Center performance and timeline objectives should include a Gantt chart depicting the five-year critical path of the Center's program. Milestones should include detailed quantitative criteria by which milestone achievement will be assessed. Include milestones and timelines for open-science sharing of data, methods and tools.

    ii. Resources: Describe the institutional resources that are available to support the specific kinds of research conducted at the Center (i.e., translational research and drug development).  

    Letters of Support: An institution applying for an Alzheimer Center for Discovery of New Medicines should demonstrate a commitment to the Center's success. Letter(s) of support from senior administration officials or other institutional officials from the PD(s)/PI(s)'s institution(s) should be provided. The letter(s) should describe the level of institutional support for the Center including any leveraged funding or resources that may be provided by the institution(s). All letters of the support for Overall component should be uploaded as a single attachment.

    Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

    All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

    Appendix:

    Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions. Do not use the Appendix to circumvent page limits.  

    PHS Human Subjects and Clinical Trials Information (Overall)

    When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

    If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

    Study Record: PHS Human Subjects and Clinical Trials Information

    All instructions in the SF424 (R&R) Application Guide must be followed

    Delayed Onset Study

    All instructions in the SF424 (R&R) Application Guide must be followed

    PHS Assignment Request Form (Overall)

    All instructions in the SF424 (R&R) Application Guide must be followed. 

    Administrative and Data Management Core

    When preparing your application, use Component Type 'Admin Core.'

    All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

    SF424 (R&R) Cover (Administrative and Data Management Core)

    Complete only the following fields:

    • Applicant Information
    • Type of Applicant (optional)
    • Descriptive Title of Applicant's Project
    • Proposed Project Start/Ending Dates
    PHS 398 Cover Page Supplement (Administrative and Data Management Core)

    Enter Human Embryonic Stem Cells in each relevant component.

    Research & Related Other Project Information (Administrative and Data Management Core)

    Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

    Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

    Project Narrative:  Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

    Project /Performance Site Location(s) (Administrative and Data Management Core)

    List all performance sites that apply to the specific component.

    Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

    Research & Related Senior/Key Person Profile (Administrative and Data Management Core)
    • In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Administrative and Data Management Core Lead' and provide a valid eRA Commons ID in the Credential field.
    • In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
    • Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
    • If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.   
    Budget (Administrative and Data Management Core)

    Budget forms appropriate for the specific component will be included in the application package.

    Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

    PHS 398 Research Plan (Administrative and Data Management Core)

    Specific Aims: Describe concisely the plans of the proposed Administrative Core leadership and explain the Core Head's specific roles and responsibilities in the management of the Center. The Administrative Core will conduct oversight for the sharing of tools, reagents, methods and data, both within the Center and with the external scientific community. Refer to the Center Organization pdf diagram attached in the Overall component. Describe plans to create and manage a publicly available database housing data generated by the Center   

    Research Strategy: The Administrative and Data Management Core will provide multidisciplinary scientific leadership for the Center by PDs/PIs, who will have expertise in specific areas of research. This Core will effectively coordinate interactions and collaborations of the Cores and external programs (i.e., AMP-AD) and investigators, as well as coordinate activities with the NIH Program Official. The application should clearly define the management plan for the Center and how it will support achievement of the proposed goals and milestones. The application should also describe the plans for evaluation of progress across the Center and communication strategies to manage and track progress of the multiple Cores. Describe the strategies and web-based platform for rapid, open-access dissemination of data and for rapid distribution of all tools and methods for their use by the scientific community. Indicate how the Core will develop methods to track experiments, document workflows and link data generated by the Core to the Center database. Describe how the Core will conduct oversight for these open-science activities. Provide a five-year timeline depicting Core goals, with milestones and detailed quantitative criteria by which milestone achievement will be assessed.   

    Additional items to be addressed:

    i. Describe the Steering Committee. Include plans to convene this group. The committee should include: the PD(s)/PI(s), Core heads, the NIH Project Scientist, the NIH Program Official (ex officio) and, if necessary, external scientists. This committee will make the following key decisions: selection and effective prioritization of candidate drug targets for experimental validation and target enablement; selection and prioritization of candidate drug targets for drug discovery; evaluation and prioritization of lead candidates generated by the Medicinal Chemistry Core for entry into animal model efficacy studies and for further drug development activities.

    ii. Describe the External Advisory Board. Include plans to appoint and convene this group of up to five members, from outside the Center, at least once per year and to document its findings and recommendations as well as the Center's changes in direction or approaches made in response. Potential new members should not be solicited or identified in the application

    Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

    All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

    Appendix:

    Limited items are allowed in the Appendix.Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions. Do not use the Appendix to circumvent page limits.  

    PHS Human Subjects and Clinical Trials Information (Administrative and Data Management Core)

    When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

    If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

    Study Record: PHS Human Subjects and Clinical Trials Information

    All instructions in the SF424 (R&R) Application Guide must be followed

    Delayed Onset Study

    All instructions in the SF424 (R&R) Application Guide must be followed

    Bioinformatics and Computational Biology Core

    When preparing your application in ASSIST, use Component Type 'Core.'

    All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

    SF424 (R&R) Cover (Bioinformatics and Computational Biology Core)

    Complete only the following fields:

    • Applicant Information
    • Type of Applicant (optional)
    • Descriptive Title of Applicant's Project
    • Proposed Project Start/Ending Dates

    PHS 398 Cover Page Supplement (Bioinformatics and Computational Biology Core)

    Enter Human Embryonic Stem Cells in each relevant component.

    Research & Related Other Project Information (Bioinformatics and Computational Biology Core)

    Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

    Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

    Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

    Project/Performance Site Location(s) (Bioinformatics and Computational Biology Core)

    List all performance sites that apply to the specific component.

    Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

    Research & Related Senior/Key Person Profile (Bioinformatics and Computational Biology Core)

    • In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Bioinformatics and Computational Biology Core Lead' and provide a valid eRA Commons ID in the Credential field.
    • In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
    • Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
    • If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.   

    Budget (Bioinformatics and Computational Biology Core)

    Budget forms appropriate for the specific component will be included in the application package.

    Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

    PHS 398 Research Plan (Bioinformatics and Computational Biology Core)

    Specific Aims: Describe concisely the plans of the proposed Core in achieving the overarching goals of the Center, specifically its role in the identification and prioritization of candidate drug targets for characterization, experimental validation, and eventual entry into drug discovery campaigns. Describe concisely the Specific Aims of the Core and explain how the Core will interact with the other Cores of the Center. Refer to the Center Organization pdf diagram attached in the Overall component. 

    Research Strategy: The Bioinformatics and Computational Biology Core will develop and deploy analytical tools and methods that enable the identification and prioritization of candidate drug targets for experimental validation and entry into drug discovery. The application should specifically describe the pipeline of bioinformatic and computational strategies, tools and methods that will be used to analyze and interpret the high-dimensional data emanating from the AMP-AD/AMP-AD Wall of Targets platform and other target discovery programs.  Indicate how the Core will collect, analyze and integrate additional data, obtained from other NIH/NIA-funded infrastructure programs (e.g., MODEL-AD, ADSP, NIAGADS, ADGC, ADNI) that will assist the Core in reaching its goals. Describe how these analyses will inform selection and prioritization of candidate drug targets for characterization and experimental validation. Provide a plan to develop methods to track experiments, document workflows and link data generated by the Core to the Center database.

    Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

    All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

    Appendix:

    Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions. Do not use the Appendix to circumvent page limits.

    PHS Human Subjects and Clinical Trials Information (Bioinformatics and Computational Biology Core)

    When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

    If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

    Study Record: PHS Human Subjects and Clinical Trials Information

    All instructions in the SF424 (R&R) Application Guide must be followed

    Delayed Onset Study

    All instructions in the SF424 (R&R) Application Guide must be followed.

    Structural Biology Core

    When preparing your application in ASSIST, use Component Type 'Core.'

    All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

    SF424 (R&R) Cover (Structural Biology Core)

    Complete only the following fields:

    • Applicant Information
    • Type of Applicant (optional)
    • Descriptive Title of Applicant's Project
    • Proposed Project Start/Ending Dates

    PHS 398 Cover Page Supplement (Structural Biology Core)

    Enter Human Embryonic Stem Cells in each relevant component.

    Research & Related Other Project Information (Structural Biology Core)

    Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

    Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

    Project Narrative:  Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

    Project /Performance Site Location(s) (Structural Biology Core)

    List all performance sites that apply to the specific component.

    Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

    Research & Related Senior/Key Person Profile (Structural Biology Core

    • In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Structural Biology Core Lead' and provide a valid eRA Commons ID in the Credential field.
    • In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
    • Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
    • If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.   

    Budget (Structural Biology Core)

    Budget forms appropriate for the specific component will be included in the application package.

    Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

    PHS 398 Research Plan (Structural Biology Core)

    Specific Aims: Describe concisely the plans of the proposed Core in achieving the overarching goal of the Center, specifically its role in the experimental characterization and validation of candidate drug targets nominated and prioritized by the Bioinformatics and Computational Biology Core. Describe concisely the Specific Aims of the Core and explain how the Core will interact with the other Cores of the Center. Refer to the Center Organization pdf diagram attached in the Overall component. 

    Research Strategy: The Structural Biology Core will develop high-quality reagents, tools and methods that support Target Enabling Packages (TEPs) for the experimental characterization, validation and, eventual translation of candidate targets into drug discovery campaigns. Describe the Core's pipeline to determine the structures, biochemical and biophysical properties of the candidate targets nominated/prioritized by the Bioinformatics and Computational Biology Core. Delineate the reagents, tools and methods that will support Target Enabling Packages (TEPS) for characterization and experimental validation of candidate targets. Describe the experimental approaches for characterizing and validating candidate targets. Describe how the Core's activities and analyses will inform selection of candidate drug targets for entry into drug discovery. Describe interactions with the Assay Development Core in developing assays that enable the characterization and validation of candidate targets. Provide a plan to develop methods to track experiments, document workflows and link data generated by the Core to the Center database.

    Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

    All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

    Appendix:

    Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions. Do not use the Appendix to circumvent page limits.

    PHS Human Subjects and Clinical Trials Information (Structural Biology Core)

    When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

    If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

    Study Record: PHS Human Subjects and Clinical Trials Information

    All instructions in the SF424 (R&R) Application Guide must be followed.

    Delayed Onset Study

    All instructions in the SF424 (R&R) Application Guide must be followed.

    Assay Development and High Throughput Screening Core

    When preparing your application in ASSIST, use Component Type 'Core.'

    All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

    SF424 (R&R) Cover (Assay Development and High Throughput Screening Core)

    Complete only the following fields:

    • Applicant Information
    • Type of Applicant (optional)
    • Descriptive Title of Applicant's Project
    • Proposed Project Start/Ending Dates

    PHS 398 Cover Page Supplement (Assay Development and High Throughput Screening Core)

    Enter Human Embryonic Stem Cells in each relevant component.

    Research & Related Other Project Information (Assay Development and High Throughput Screening Core)

    Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

    Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

    Project Narrative:  Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

    Project /Performance Site Location(s) (Assay Development and High Throughput Screening Core)

    List all performance sites that apply to the specific component.

    Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

    Research & Related Senior/Key Person Profile (Assay Development and High Throughput Screening Core)

    • In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Assay Development Core Lead' and provide a valid eRA Commons ID in the Credential field.
    • In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
    • Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
    • If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.   

    Budget (Assay Development and High Throughput Screening Core)

    Budget forms appropriate for the specific component will be included in the application package.

    Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

    PHS 398 Research Plan (Assay Development and High Throughput Screening Core)

    Specific Aims: Describe concisely the plans of the proposed Core in achieving the overarching goal of the Center, specifically its role in developing assays, screening modalities, and data analysis methods that will enable the characterization and experimental validation of candidate targets and support drug discovery campaigns. Describe concisely the Specific Aims of the Core and explain how the Core will interact with the other Cores of the Center. Refer to the Center Organization pdf diagram attached in the Overall component.

    Research Strategy: The Assay Development and High Throughput Screening Core will develop innovative assay and screening methods to enable a wide range of the Center's activities, including characterization and experimental validation of candidate targets and drug discovery. Describe the different assay platforms the Core will use to assess ligand binding, enzyme activity, biochemical and biophysical properties, target modulation, molecular probe discovery, identification of hit compounds, Structure-Activity Relationship (SAR) studies, and cytotoxicity profiling of hits and lead compounds. Describe the experimental approaches for the design, optimization, validation and, if necessary, miniaturization of screens and assays. Describe assay panels supporting HTS hit validation and Structure-Activity Relationship (SAR) studies. Describe interactions with the Structural and Chemical Biology Core in developing assays that enable the characterization and validation of candidate targets. Describe interactions with the Medicinal Chemistry and Chemical Biology Core in developing assay strategies for molecular probe discovery, the identification and validation of chemical hits, and SAR studies. Provide a plan to develop methods to track experiments, document workflows and link data generated by the Core to the Center database.

    Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

    All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

    Appendix:

    Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions. Do not use the Appendix to circumvent page limits.

    PHS Human Subjects and Clinical Trials Information (Assay Development and High Throughput Screening Core)

    When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

    If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

    Study Record: PHS Human Subjects and Clinical Trials Information

    All instructions in the SF424 (R&R) Application Guide must be followed.

    Delayed Onset Study

    All instructions in the SF424 (R&R) Application Guide must be followed.

    Medicinal Chemistry and Chemical Biology Core

    When preparing your application in ASSIST, use Component Type 'Core.'

    All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

    SF424 (R&R) Cover (Medicinal Chemistry and Chemical Biology Core)

    Complete only the following fields:

    • Applicant Information
    • Type of Applicant (optional)
    • Descriptive Title of Applicant's Project
    • Proposed Project Start/Ending Dates

    PHS 398 Cover Page Supplement (Medicinal Chemistry and Chemical Biology Core)

    Enter Human Embryonic Stem Cells in each relevant component.

    Research & Related Other Project Information (Medicinal Chemistry and Chemical Biology Core)

    Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

    Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

    Project Narrative:  Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

    Project /Performance Site Location(s) (Medicinal Chemistry and Chemical Biology Core)

    List all performance sites that apply to the specific component.

    Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

    Research & Related Senior/Key Person Profile (Medicinal Chemistry and Chemical Biology Core)

    • In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Medicinal Chemistry and Chemical Biology Core Lead 'and provide a valid eRA Commons ID in the Credential field.
    • In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
    • Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
    • If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.   

    Budget (Medicinal Chemistry and Chemical Biology Core)

    Budget forms appropriate for the specific component will be included in the application package.

    Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

    PHS 398 Research Plan (Medicinal Chemistry and Chemical Biology Core)

    Specific Aims: Describe concisely the plans of the proposed Core in achieving the overarching goals of the Center, specifically its role in molecular probe development and drug discovery for selected and validated candidate AD targets. Describe the Specific Aims of the Core and explain how the Core will interact with the other Cores of the Center. Refer to the Center Organization pdf diagram attached in the Overall component. 

    Research Strategy: The Medicinal Chemistry and Chemical Biology Core will provide molecular probe development and drug discovery expertise to the Center. Describe tools and methods available for the following: custom library development; in silico virtual ligand screening and profiling; cheminformatic approaches for analysis of hits and lead candidates; computational docking studies and analyses; structure-based design of molecules and synthetic medicinal chemistry to optimize molecular probes and lead compounds; fragment-based drug discovery; determination of structures (NMR, MS, etc.); 3-D molecular modelling; exploratory pharmacology; and early toxicology profiling. Indicate available chemical libraries for robotic and in silico screening. Describe experimental approaches for molecular probe development. Describe chemical biology approaches to selectively modulate the activity of candidate drug targets. Describe experimental approaches for hit-to-lead optimization of drug-like properties, potency, target selectivity, and pharmacological properties. For SAR studies, including ADMET, provide a typical testing funnel. Describe interactions with the Structural Biology Core in developing molecular probes for target validation/enablement. Describe interactions with the Assay Development Core in developing assay strategies for molecular probe discovery, the identification and validation of chemical hits, and SAR studies. Provide a plan to develop methods to track experiments, document workflows and link data generated by the Core to the Center database .

    Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

    All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

    Appendix:

    Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions. Do not use the Appendix to circumvent page limits.

    PHS Human Subjects and Clinical Trials Information (Medicinal Chemistry and Chemical Biology Core)

    When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

    If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

    Study Record: PHS Human Subjects and Clinical Trials Information

    All instructions in the SF424 (R&R) Application Guide must be followed

    Delayed Onset Study

    All instructions in the SF424 (R&R) Application Guide must be followed

    3. Unique Entity Identifier and System for Award Management (SAM)

    See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.

    4. Submission Dates and Times

    Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

    Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies) using ASSIST or other electronic submission systems. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH's electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

    Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

    Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

    5. Intergovernmental Review (E.O. 12372)

    This initiative is not subject to intergovernmental review.

    6. Funding Restrictions

    All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

    Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

    7. Other Submission Requirements and Information

    Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.

    For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

    Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

    For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

    Important reminders:

    All PD(s)/PI(s) and component Project Leads must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

    The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization's profile in the eRA Commons and for the System for Award Management (SAM). Additional information may be found in the SF424 (R&R) Application Guide.

    See more tips for avoiding common errors.

    Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

    In order to expedite review, applicants are requested to notify the NIA Referral Office by email at ramesh.vemuri@nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application. 

    Post Submission Materials

    Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

    Section V. Application Review Information
    1. Criteria

    Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

    For this specific announcement, note the following:

    Reviewers will provide an overall impact score for the entire Alzheimer's Disease Center (Overall Component) and for each individual Core. In addition, assigned reviewers will provide individual "criterion scores" for the Overall criteria, but not for the other components.

    The Administrative Core and Resource Cores will be evaluated, but each will receive only one overall rating.

    Overall Impact - Overall

    Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Alzheimer Center for Discovery of New Medicines to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the Center proposed).

    Scored Review Criteria - Overall Center

    Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a Center that by its nature is not innovative may be essential to advance a field.

    Significance

    Does the Center address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the Center are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

    Specific for this FOA: What is the likelihood that the proposed research will achieve the overarching goals of the Center: to improve, reinvigorate and diversify the AD drug development pipeline, and to promote rapid dissemination of all data, methods and tools to all qualified researchers for their use in advancing AD drug discovery and understanding of AD disease biology? What is the likelihood that the research of the proposed Center will substantially de-risk AD therapeutics development to the point that biopharma will increase its investment, accelerating the delivery of new drugs to AD patients?

    Investigator(s)

    Are the PD(s)/PI(s), collaborators, and other researchers well suited to the Center? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI , do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

    Specific for this FOA:  To what extent do key personnel in the Center have expertise in bioinformatics, computational biology, disease biology, structural genomics, assay development, medicinal chemistry, pharmacology, pre-clinical therapy development and, clinical research? How well is the proposed team-science justified as being essential to achieving the stated goals of the Center? To what extent do the Center Program Director/Principal Investigator (PD/PI) and Core Leaders have a record of directing translational, preclinical therapy development and/or clinical research?

    Innovation

    Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

    Specific for this FOA: How well does the overall program incorporate innovative concepts and approaches? Is the proposed science sufficiently innovative to successfully characterize, validate and enable candidate therapeutic targets and initiate drug discovery campaigns against these targets? To what extent are the proposed strategies and infrastructure for rapid, open science sharing of data, methods, and tools innovative?

    Approach

    Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Center? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed?  Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

    If the Center involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

    Specific for this FOA: Is there a clear Center organizational diagram that depicts interactions of key components within and external to the Center? How well are the Center components and the investigator team integrated to collectively support the overarching goals of the Center? Is there evidence of robust, multidirectional interactions between the Cores? How well does the proposed Center take advantage of multidisciplinary approaches to develop a comprehensive program that includes the characterization, validation, and enablement of candidate therapeutic targets and launching of drug discovery campaigns against enabled targets? Is there a clear plan to use and analyze target-related data available from AMP-AD/AMP-AD Wall of Targets and other NIH/NIA funded data bases? Is there an acceptable strategy describing the open access sharing of data, methods, assays and tools generated by the Center? Have clear timelines and yearly milestones been established for the Center program? To what extent is the timeline feasible given the organization and goals of the Center?    

    Environment

    Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

    Specific for this FOA: Are effective mechanisms in place to foster strong collaborative interactions and promote "cross-fertilization" among Center investigators and participating institutions? Is there evidence of multi-directional interactions between the Cores? If applicable, how well do the multi-institutional teams take advantage of the distinctive strengths available through multi-institutional collaborations? How well do the institutional resources support the specific needs of translational research and drug development? 

    Additional Review Criteria - Overall

    As applicable for the Center proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

    Protections for Human Subjects

    For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

    For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

    Inclusion of Women, Minorities, and Children 

    When the proposed Center involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed.  For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

    Vertebrate Animals

    The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

    Biohazards

    Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

    Resubmissions

    Not Applicable

    Renewals

    Not Applicable

    Revisions

    Not Applicable

    Additional Review Considerations - Overall Center

    As applicable for the Center proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

    Applications from Foreign Organizations

    Not Applicable

    Select Agent Research

    Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

    Resource Sharing Plans

    Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genomic Data Sharing Plan .


    Authentication of Key Biological and/or Chemical Resources

    For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

    Budget and Period of Support

    Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

    Review Criteria-Cores

    Reviewers will provide an overall impact score for the Administrative Core and Resource Cores to reflect their assessment of the scientific and technical merit of each Core. The following items for each Core should be evaluated. However, criterion scores will not be provided for the Cores.

    For the Administrative and Data Management Core

    • Is the proposed Administrative and Data Management Core adequate to accomplish the objectives of the overall program?
    • Do the Core's administrative, management, and leadership capabilities adequately provide for internal quality control of ongoing research, management of day-to-day program activities, effective communication and cooperation among PDs/PIs, and resolution of conflicts?
    • How well does the Core synergize the interactions, approaches and collaborations within the Center?
    • Is there an effective plan to coordinate interactions and collaborations of the Center with external programs, such as AMP-AD/AMP-AD Wall of Targets, and external investigators?
    • Are the mechanisms for the evaluation of milestone achievement across the Center and communication strategies to manage and track progress sound and robust?
    • Are there adequate plans for ensuring appropriate prioritization of Center activities?
    • Does the proposed Administrative and Data Management Core PD/PI have experience in research administration, coordination and data management?
    • Is there a logical plan for designing and maintaining both an internal facing and publicly available, open science data base/platform housing data generated by the Center?
    • Is there an adequate strategy describing the open access sharing of data, methods, assays and tools generated by the Center?
    • To what extent is the planned oversight for the open-access sharing of data, methods, assays and tools with the external scientific community appropriate to the overarching goals of the Center and needs of the community?
    • Are plans to convene a Steering Committee presented and are the activities of the Steering Committee clearly described?
    • Are the plans to appoint and convene an External Advisory Board presented and are the activities of the External Advisory Board clearly described? 
    • What is the likely effectiveness of the utilization of the Steering Committee and External Advisory Board in conducting oversight and monitoring of different aspects of the Center's function?
    • Is there a sufficiently detailed five-year timeline depicting Center goals and yearly milestones with quantitative success criteria?

    For the Bioinformatics and Computational Biology Core

    • Is the proposed Bioinformatics and Computational Biology Core adequate to accomplish the objectives of the overall program?
    • Is there a clear description of the Core's pipeline of bioinformatic and computational strategies, tools and methods that will be used to analyze and interpret the high-dimensional data emanating from the AMP-AD/AMP-AD Wall of Targets and other target discovery programs?
    • Is there a clear description of how the Core's activities and analyses will inform the identification and prioritization of candidate drug targets for further characterization and entry into drug discovery campaigns?
    • Are the proposed bioinformatic and computational strategies, tools, methods and analyses well-reasoned, appropriate, and sufficiently cutting-edge to accomplish the specific aims of the Core?
    • Are potential problems, alternative strategies, and benchmarks for success presented?
    • Are the interactions of the Core with other units of the Center well described?
    • Are the collaborations of the Core with existing NIH and NIA infrastructure/databases: AMP-AD, MODEL-AD, ADSP, NIA CGAD, ADGC, and ADNI well described?
    • Does the proposed Bioinformatics and Computational Biology Core PD/PI have experience in bioinformatics and/or computational biology?
    • Are the qualifications, experience, and commitment of the other core personnel appropriate?
    • Is the plan to develop methods to track experiments, document workflows and link data generated by the Core to the Center database adequate?

    For the Structural Biology Core

    • Is the proposed Structural Biology Core adequate to accomplish the objectives of the overall program?
    • Is there a clear description of the Core's pipeline to determine the structures, biochemical and biophysical properties of the candidate targets?
    • Are the reagents, tools, methods and analyses that will support Target Enabling Packages (TEPS) for characterization and experimental validation of candidate targets, well-reasoned, appropriate and sufficiently cutting edge?
    • Is there a clear description of how the Core's activities and analyses will inform selection of candidate drug targets for entry into drug discovery?
    • Are potential problems, alternative strategies, and benchmarks for success presented?
    • Is there a clear description of the infrastructure available to the Core for the execution of its specific aims?
    • Are the interactions of the Core with other units of the Center well described, specifically interactions with the Assay Development and Medicinal Chemistry and Chemical Biology Cores?
    • Does the proposed Structural Biology Core PD/PI have experience in structural biology?
    • Are the qualifications, experience, and commitment of the other core personnel appropriate?
    • Is the plan to develop methods to track experiments, document workflows and link data generated by the Core to the Center database adequate?

    For the Assay Development and High Throughput Screening Core

    • Is the proposed Assay Development and High Throughput Screening Core adequate to accomplish the objectives of the overall program?
    • Is there a clear description of the Core's assay development pipeline that will be used to enable the characterization and experimental validation of candidate targets and support drug discovery campaigns?
    • Is there a clear description of the experimental approaches that will be employed for the design, optimization, validation and, if necessary, miniaturization of screens and assays?
    • Are the assays, screening modalities and data analysis methods cutting edge?
    • Are potential problems, alternative strategies, and benchmarks for success presented?
    • Is there a clear description of the infrastructure available to the Core for assays, screens and data analysis?
    • Are the interactions of the Core with other units of the Center well described, specifically interactions with the Structural Biology and Medicinal Chemistry and Chemical Biology Cores?
    • Does the proposed Assay Development and High Throughput Screening Core PD/PI have experience in assay development and/or high throughput screening?
    • Are the qualifications, experience, and commitment of the other core personnel appropriate?
    • Is the plan to develop methods to track experiments, document workflows and link data generated by the Core to the Center database adequate?

    For the Medicinal Chemistry and Chemical Biology Core:

    • Is the proposed Medicinal Chemistry and Chemical Biology Core adequate to accomplish the objectives of the overall program?
    • Is there a clear description of the Core's pipeline for the development of molecular probes for drug target characterization/validation and drug discovery through hit-to-lead medicinal chemistry?
    • Is there a clear description of experimental approaches for molecular probe development?
    • Are the strategies for incorporating chemical biology approaches to characterize and experimentally validate candidate drug targets well-reasoned and appropriate?
    • Is there a clear description of experimental approaches for hit-to-lead optimization of drug-like properties, potency, target selectivity and early pharmacological profiling?
    • Is there a clear description of experimental approaches for molecular probe development?
    • Are potential problems, alternative strategies, and benchmarks for success presented?
    • Are the reagents, tools, methods and analyses that will support molecular probe development and drug discovery well-reasoned, appropriate and sufficiently cutting edge?
    • Is there a clear description of the infrastructure available to the Core for the prosecution of its specific aims?
    • Are the interactions of the Core with other units of the Center well described, specifically interactions with the Structural Biology and Assay Development Cores?
    • Does the proposed Medicinal Chemistry and Chemical Biology Core PD/PI have experience in medicinal chemistry and drug discovery?
    • Are the qualifications, experience, and commitment of the other core personnel appropriate?
    • Is the plan to develop methods to track experiments, document workflows and link data generated by the Core to the Center database adequate?
    2. Review and Selection Process

    Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by the National Institute on Aging in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

    As part of the scientific peer review, all applications:

    • May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
    • Will receive a written critique.

    Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

    Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council on Aging. The following will be considered in making funding decisions:

    • Scientific and technical merit of the proposed project as determined by scientific peer review.
    • Availability of funds.
    • Relevance of the proposed project to program priorities.  
    3. Anticipated Announcement and Award Dates

    After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

    Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

    Section VI. Award Administration Information
    1. Award Notices

    If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

    A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee's business official.

    Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

    Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

    Milestones

    Annual milestones, with accompanying success criteria, will be included in the Special Terms and Conditions of the Notice of Award. Failure to meet these annual milestones may delay or reduce the next year's award. In addition to milestones, the decision regarding continued funding will also be based on the overall progress of the Center.   

    2. Administrative and National Policy Requirements

    All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

    Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person's race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency.  HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator's scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

    For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

    In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements.  FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award.  An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS.  The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant's integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 "Federal awarding agency review of risk posed by applicants."  This provision will apply to all NIH grants and cooperative agreements except fellowships.

    Cooperative Agreement Terms and Conditions of Award

    The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

    The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the purpose of NIH is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

    The PD(s)/PI(s) will have the primary responsibility for:

    • Determining experimental approaches, designing protocols, conducting experiments, and analyzing and interpreting research data for studies funded through this U54.  The PD/PI is ultimately responsible for the project and will make the final decisions regarding all project plans, provided that they can be executed within NIA/NIH-approved budgets and according to NIA/U54 grant and contract policies;
    • Leading the project as a whole and agreeing to accept close assistance, advice, coordination, and collaborate with the NIA Project Scientist and other awardees;
    • Ensuring active participation of partner sites and collaborators in group activities, if applicable;
    • Initial development and proposal of annual milestones, success criteria and timeline towards the characterization and validation of candidate therapeutic targets and development of the therapeutic(s) that will be achieved during the project period;
    • Submitting annual milestone reports in a standard format, as agreed upon by the NIA;
    • Formation of a Center Steering Committee which will serve as the operational governing board of the project. The Center Steering Committee should include: the PD(s)/PI(s), Core leads, the NIH Project Scientist (voting) and external scientists (s) (if required);
    • Organizing and conducting meetings of the Center Steering Committee, either by video-conference or face-to-face, to discuss progress with an interval to be determined by the NIA; 
    • Accepting and implementing Center Steering Committee recommendations, guidelines and procedures as appropriate;
    • Formation of an External Advisory Committee which will serve as a guide to the Center leadership in assessing the progress in achieving the yearly milestones, assessing new scientific opportunities as they are presented and evaluating the effectiveness of interaction among Cores and Center participants. The members of the External Advisory Committee will be selected in consultation with NIA Program staff and will include individuals not directly involved in the Center;
    • Organizing and coordinating an annual meeting of External Advisory Committee with the Center Steering Committee, either by videoconference or face-to-face;
    • Adhering to the general NIA/NIH policies regarding sharing resources and data release, as well as the specific data and resource, tools and method-sharing policies proposed in the application, as modified by any negotiation prior to award;
    • Adhering to NIA/NIH policies, including those regarding intellectual property and publications;
    • Implementing all scientific and policy decisions approved by the NIA/NIH.

    NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

    • An NIA Project Scientist will be assigned to the project with substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice and coordination that is above and beyond the normal stewardship role in awards. The Project Scientist is a partner within the research team representing the government's interest in the substantive work of the research team.  The primary role of the Project Scientist is to facilitate the work of the awardees.

    Responsibilities of the NIA Project Scientist:

    • Participate in regular meetings with awardee and Center Steering Committee to share progress, either by teleconference, videoconference or face-to-face, and to assist in the successful prosecution of the specific aims of the U54;
    • Determine the interval of meetings with awardee and NIA staff; 
    •  Review all major transitional changes that awardees may propose and offer advice on their appropriateness prior to implementation to assure consistency with the goals of this FOA; 
    • Monitor institutional interactions between U54 awardees and investigators at other institutions, as appropriate for the program; 
    • Coordinate and facilitate the interactions among U54 awardees under this initiative;
    • Provide technical assistance, advice, and coordination to the project, although the dominant role and responsibilities for the activities funded by the U54 reside with the PI/PD

    Responsibilities of the NIA Program Official:

    Additionally, an NIA Program Official will be assigned to the project and will be responsible for monitoring progress and for the normal programmatic stewardship of the award. The NIA Program Official will be named in the award notice and will be the primary contact with the PI/PD. 

    Areas of Joint Responsibility include:

    Center Steering Committee: The awardees and the NIA Project Scientist will meet as the Center Steering Committee at least one time per year in person and monthly on video-conference calls as needed to share information on data resources, methodologies, and analytical tools, as well as data and preliminary results. The Steering Committee should include: the PD(s)/PI(s), Unit leads, the NIA Project Scientist (voting) and external scientists (s) (as required).  Key co-investigators and pre- and postdoctoral trainees, especially those who are members of under-represented groups or those from different but related disciplines, in addition to the PD/PIs, are eligible to attend these meetings.

    The Center Steering Committee will:

    • Participate in monitoring "day to day" scientific progress of the research project plan, assessing progress of the milestones;
    • Make strategic decisions with regard to goals and research implementation, including: the establishment of standard procedures and protocols, developing a prioritized portfolio of therapeutic targets for validation and drug discovery, deciding which drug target projects will be initiated by the Center, evaluation of lead candidates generated by the Center and their prioritization for entry into animal efficacy studies (MODEL-AD) and entry into other NIA/NIH drug development programs;
    • Establish shared resources and conduct oversight for open-access sharing and distribution of resources and data to all qualified scientists;
    • Establish collaborations and workgroups for specific tasks as needed, which could include representatives from scientists external to the Center and the NIA/NIH;
    • Meet annually with the External Advisory Committee, or as dictated by the needs of the Project.

    External Advisory Committee: In consultation with NIA staff, an external committee of advisors will be selected, to be comprised of individuals not directly involved in the Center 

    The External Advisory Committee will:

    • Guide the Center leadership in assessing the Center's progress in achieving the yearly milestones;
    • Assess new scientific opportunities as they are presented;
    • Evaluate the effectiveness of interaction among Cores and Center participants;
    • Advise Center leadership on changes in direction or approach; sharing of tools, methods and data; and problem identification and resolution.

    Dispute Resolution:
    Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

    3. Reporting

    When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

    A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

    The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement.  

    In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.

    Section VII. Agency Contacts

    We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

    Application Submission Contacts

    eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten on-time submission, and post-submission issues)

    Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
    Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

    General Grants Information (Questions regarding application processes and NIH grant resources)
    Email: GrantsInfo@nih.gov (preferred method of contact)
    Telephone: 301-945-7573

    Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
    Contact Center Telephone: 800-518-4726
    Email: support@grants.gov

    Scientific/Research Contact(s)

    Lorenzo M. Refolo. Ph.D
    National Institute on Aging (NIA)
    Telephone: 301-594-7576
    Email: refolol@mia.nih.gov

    Peer Review Contact(s)

    Ramesh Vemuri, Ph.D.
    National Institute on Aging (NIA)
    Telephone: 301-402-7700
    Email: ramesh.vemuri@nih.gov

    Financial/Grants Management Contact(s)

    Jessi Perez
    National Institute on Aging(NIA)
    Telephone: 301-402-7739
    Email: jessi.perez@nih.gov

    Section VIII. Other Information

    Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

    Authority and Regulations

    Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.    

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