Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization.

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.

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

It is critical that applicants follow the Multi-Project (M) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the NOFO) 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.

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Overview

This NOFO invites U54 Cooperative Agreement applications aiming to establish multi-component AD/ADRD MPS Translational Centers to develop 2D and 3D models of AD/ADRD as reproducible and scalable platforms that recapitulate key features of human AD/ADRD pathophysiology to be used as precision medicine research tools to investigate the complex biology of AD/ADRD and to accelerate multiple aspects of drug discovery and preclinical drug development. The Centers will focus on the development and validation of 2D and 3D MPS models of AD/ADRD, conduct extensive characterization and deep phenotyping of these 2D and 3D MPS models, discover and characterize translatable biomarkers, and develop standardized methods to facilitate the assessment of bioavailability, efficacy, and toxicity of candidate therapeutic agents. Central to this initiative are the rapid dissemination of 2D and 3D MPS models and transparent reporting of research methodology and preclinical safety and efficacy testing findings to all qualified researchers for their use in basic research and preclinical therapy development. To achieve these goals, the Centers will need to bring together experts in AD/ADRD disease biology, bioengineering, microfluidics, material science, systems biology, computational biology, electrophysiology, pharmacology, biostatistics, and clinical science.

Background

This NOFO is issued as an initiative tied to the implementation of several research milestones that are part of the AD/ADRD research framework to advance the development of precision medicines for AD/ADRD in support of the National Plan to Address Alzheimer’s and Related Dementias .

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly, affecting more than 35 million people worldwide. In the United States, it is estimated that over 5 million people are currently diagnosed with AD, the prevalence of which is predicted to rise to more than 15 million by 2050. The disease currently costs the U.S. healthcare system an estimated $200 billion per year.

The development of effective AD/ADRD therapies continues to be challenging, as evidenced by the extremely high attrition rate of AD drug candidates in the clinic, with 98% of therapies failing in Phase III. One reason for this high attrition is the poor predictive power of preclinical studies performed in AD transgenic mouse models. While animal testing is the gold standard for preclinical drug development, species differences combined with the complexity and heterogeneity of AD/ADRD contribute to the insufficient predictive value of animal model safety and efficacy studies and the high attrition of new investigational drugs during clinical development. To address the preclinical to clinical development gap, the National Institute on Aging (NIA) has established the MODEL-AD Translational Centers, whose mission is to develop the next generation of mouse models that better recapitulate the features of late-onset AD (LOAD) and to provide infrastructure for rigorous and reproducible preclinical efficacy testing of promising therapeutic candidates. There remains, however, a critical need for the development of more predictive in vitro and ex-vivo AD/ADRD models as reproducible and scalable platforms that can recapitulate key features of human pathophysiology and can be used as precision medicine research tools to investigate the complex biology of AD/ADRD and advance multiple steps of the drug development process.

MPS are in vitro models with interconnected sets of 2D or 3D cellular constructs made with immortalized cell lines, primary cells, or induced pluripotent stem cells (iPSCs). 2D systems are often composed as a cellularly homogeneous monolayer, while the more advanced 3D systems, including tissue chips, can contain multiple cell types and multi-organ systems. Each platform design, from 2D to 3D engineered systems, has advantages and disadvantages. Therefore, the selection of a particular platform will depend on the context of its use, including the characteristics of the assays and their readouts. MPS platforms offer the advantages of providing an unprecedented physiological accuracy for the study of cell-cell, drug-cell, and organ-drug interactions. Ultimately, these strategies can be foundational for the development of precision medicines for AD/ADRD that will enable rapid and high-fidelity evaluation of safety and efficacy for candidate therapeutics.

The AD/ADRD MPS Translational Centers established through this funding opportunity are envisioned as a key component of NIA’s AD/ADRD Translational Program. Operating under open science principles, NIA’s AD/ADRD Translational Program is focused on enriching the AD/ADRD therapeutic pipeline by: (1) supporting the development of Investigational New Drugs (INDs) for a diverse portfolio of therapeutic targets, and (2) enabling a precision medicine approach to drug development through an array of systems biology consortia for AD/ADRD target and biomarker discovery and translational centers for development of new models and advancement of novel targets into drug discovery. All data and research tools developed by these programs are available to the academic and industry research community via the AD Knowledge Portal, a centralized, NIA-supported FAIR data infrastructure.

The AD/ADRD MPS Translational Centers will complement the capabilities of NIA’s AD/ADRD Translational Program and the robust and longstanding NIH investment in the NIH Tissues-on-Chips program led and managed by the National Center for Advancing Translational Sciences (NCATS). Interactions with these consortia are encouraged.

Research Objectives and Scope

The overarching objective of this initiative is to create AD/ADRD MPS Translational Centers focused on establishing an infrastructure to develop standardized and deeply phenotyped 2D and 3D MPS models, establishing the translational validity of these MPS models to recapitulate the molecular and network perturbations identified in AD/ADRD, and ensuring rapid and broad distribution of the MPS models, data, and analytical methods for use in basic research and therapy development.

The AD/ADRD 2D and 3D MPS models are expected to express critical aspects of human physiology and provide a measurable output for the representative systems. In developing AD/ADRD disease models that more accurately represent human physiology and pathology, investigators are strongly encouraged to take advantage of recent advances with iPSCs. Essential characteristics of the disease models should include all or some of the following features:

1. Recapitulate the complexity of the human brain;
2. Recreate the neurodegenerative microenvironment;
3. Reflect the heterogeneity and complexity of the disease;
4. Accurately predict therapy efficacy and safety in humans; and
5. Enable rigorous preclinical efficacy and safety testing.

Ideally, the platform used should be compatible with high content screening platforms that include multiple molecular read-outs, such as gene expression, proteomic, metabolomic, or epigenomic analyses. The bioengineered platform should also provide spatial and temporal control of the cellular microenvironment, while enabling continuous monitoring (sensing), probing (direct in-cell measurements), and sampling (testing and continuous data collection and analysis) of the system. Proposals to develop MPS technologies that allow for the testing of potential AD/ADRD therapies in a manner that incorporates development of collections from participants from diverse ancestry and genetic backgrounds are encouraged. It is anticipated that development of MPS representative of human tissues and organs will lead to a reduction in the timelines and costs associated with therapeutic development, and will lead to enhanced efficacy and toxicity information for regulatory decisions.

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

• Development of 2D and 3D culture system prototypes that recapitulate human AD/ADRD, including tissue chips that can contain multiple cell types and multi-organ systems
• Development of standardized protocols to enable validated and reproducible culture of cells in 2D and 3D microenvironments
• Development of evaluation metrics and criteria to assess if the MPS microenvironment is representative of the human AD/ADRD physiological environment
• Extensive characterization and deep phenotyping of 2D and 3D MPS models
• Cross-validation of the molecular, cellular, and pathologic disease model phenotypic data with multi-modal human data
• Extensive characterization and clinical-pathological staging of the disease models with the corresponding stages of clinical disease using translatable biomarkers, including biomarkers based on genomic, proteomic, metabolomic, and epigenomic signatures
• Generation and characterization of collections of iPSC cell lines and 2D/3D MPS models from individuals from diverse cohorts with various AD/ADRD phenotypes, including from individuals with specific naturally occurring mutations/risk alleles to recapitulate complex interactions in a dish and develop novel ex-vivo models of cognition in a dish and ancestry in a dish for precision medicine research
• Use of patient-derived cell lines where patient consent allows commercialization and broad sharing of cells and cellular derivatives with academic and industry researchers
• Demonstration of the ability to scale up the system for use in AD/ADRD drug discovery and drug development
• Benchmarking of the performance of therapeutic agents in the MPS systems across multiple disease-relevant outcomes (molecular, biochemical, cellular, histological phenotypes)
• Establishment of methods for rigorous preclinical safety and efficacy testing and identification of molecular and phenotypic readouts that can serve as biomarkers of target engagement, as well as biomarkers of safety and efficacy.

Also of interest is the establishment of a repository of fully characterized, quality-controlled, and fully sequenced reference iPSC lines accessible to the wide research community that can serve as:

• A standard control for healthy genotypes and for generating edited-isogenic lines carrying specific AD risk variants.
• A source of cell lines from individuals from diverse cohorts with AD-related phenotypes and specific naturally occurring mutations/risk alleles.
• A resource to test and provide reference data on protocols to generate all CNS cell types.

Applicants are expected to follow open-science, open-source principles and adhere to NIH guidelines for rigorous study design and transparent reporting to maximize the reproducibility and translatability of their findings. This includes developing strategies and web-based infrastructure for rapid, open-access dissemination of data and methodology and for rapid distribution of all models, tools, and methods.

A pplications must include appropriate support for curation and annotation of the molecular and clinical data types used and/or generated on the project to maximize the usability of the data by the broader research community. Please refer to the Resource Sharing Plan section of this NOFO for detailed guidance.

All studies should be conducted and reported in compliance with NIH guidance on rigor and reproducibility .

Applicants are strongly encouraged to contact NIA scientific/research staff during the pre-application process to discuss their prospective applications.

Applications that include the following types of studies will be considered non-responsive and will not be reviewed:

• Engineering of non-human tissue models
• Use of human fetal tissue for tissue chip development
• Development of tissues for transplantation
• Conduct of clinical trials

Overall Organization of the Center

The Center should have the following structure:

Administrative and Data Management Core: will serve as the focus for the synergistic activities of the Center and will be responsible for managing, coordinating, and supervising the entire range of Center activities. This includes monitoring progress, ensuring that the overall project management plan is effectively implemented, and ensuring that yearly milestones are achieved within proposed timelines. In addition, the Core will be responsible for maintaining both an internal and an outward-facing, publicly available website housing data generated by the Center, as well as for oversight for open-access sharing and distribution of MPS models, methods, and data to all qualified scientists from the academic and biopharma communities.

Bioinformatics and Computational Biology Core: will develop and deploy analytical tools and methods that enable the characterization and standardization of MPS models for experimental validation relative to human AD/ADRD outcomes. For this purpose, the Core will use both standard and innovative biostatistics, bioinformatics, and computational biology approaches to analyze and interpret high-dimensional data generated in the MPS models and their integration/alignment with relevant human data. The Core, in conjunction with the Administrative and Data Management Core, will share responsibility for creating and maintaining both an internal and an outward-facing, publicly available website housing data generated by the Center and ensure the rapid and broad sharing of data and analytical results.

MPS Models Development and Validation Core: will be responsible for the development, characterization, and deep phenotyping of new 2D and 3D MPS models in comparison with various molecular, biochemical, and cellular pathological features of human AD/ADRD, including representation of population heterogeneity.

Preclinical Efficacy and Safety Core: will be responsible for developing and implementing rigorous best practices for preclinical safety and efficacy testing of candidate therapeutics and testing promising preclinical candidates in AD/ADRD MPS models. Emphasis should be placed on using translatable biomarkers that inform the level of target engagement as endpoints to determine the widest possible therapeutic window that will support testing a full dose range in humans.

In addition to the Cores above, the Center should have a Steering Committee and an External Advisory Board.

The Steering Committee will consist of the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)), Core leads, and NIA/NIH program staff and will serve as the operational governing board. Among other functions, the Steering Committee will have primary responsibility for finalizing standard procedures and protocols, holding regular teleconferences, deciding on new projects, and developing a prioritized portfolio of preclinical drug candidates for testing.

The External Advisory Board will consist of 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 MPS models and data, and problem identification and resolution. The External Advisory Board will be established in collaboration with NIA program staff after the funding of the Center.

Milestones

This is a milestone-driven program to ensure research is focused on efficiently achieving a well-defined goal. 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 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 an application, NIA program staff will discuss with the applicant 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 other NIH staff 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.

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

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:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• 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)

Local 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)

Federal Governments

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

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 allowed.

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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• System for Award Management (SAM) 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.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. 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 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.

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 diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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 NOFO 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.

NIH will not accept duplicate or highly overlapping applications under review at the same time per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. 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 NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST or an institutional system-to-system solution. A button to apply using ASSIST is available in Part 1 of this NOFO. See the administrative office for instructions if planning to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the Multi-Project (M) Instructions in the How to Apply - Application Guide, except where instructed in this notice of funding opportunity 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.

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:

Zane Martin, Ph.D.
National Institute on Aging (NIA)
Email: [email protected]

Page Limitations

All page limitations 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.

Overall Component

When preparing the application, 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.

Project/Performance Site Locations (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 and Related Senior/Key Person Profile (Overall)

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this NOFO) for the entire application.

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 AD/ADRD research. Specify how the Center will improve knowledge of basic etiology of disease and preclinical and clinical therapy development. These aims should be overarching, at a high level, and distinct from the aims of the individual cores.

Research Strategy: Present a concise overall vision and plan for the proposed Center. Describe the framework for the Center, overall experimental strategy, and how the Center will address the objectives of the program. Describe the synergy to be achieved by the Center, how the Bioinformatics and Computational Biology Core and Preclinical Efficacy and Safety Core will integrate and inform the MPS Models Development and Validation Core, and how there will be multidirectional exchanges between the Cores. Describe how the cutting-edge science emanating from the Cores will help design and create advanced and predictive AD/ADRD MPS models. 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 this research will have the potential for assisting in the development of knowledge of basic etiology of disease. Describe how the Center will maintain both an internal and an outward-facing, publicly available website housing data generated by the Center. Describe how the Center will rapidly disseminate the MPS models and transparent reporting of research methodology and preclinical safety and efficacy testing findings to all qualified researchers.

Additional items to be addressed:

i. Center Organization: The overall description of the Center should explain (1) how the components of the Center, including key personnel, will interact; (2) why each component is essential for addressing the overall goal of the Center; and (3) how the Center/Cores will interact with programs external to the Center.

ii. Milestones and Timeline: The overall description of the Center performance and timeline objectives should include (1) a clear description of all interim objectives to be achieved during the course of the project; (2) detailed quantitative criteria by which milestone achievement will be assessed; and (3) a detailed timeline for the anticipated attainment of each milestone and the overall goal(s).

Letters of Support: An institution applying for funding through this solicitation should demonstrate a commitment to the center success. Letter(s) of support from senior administration officials or other institutional officials from the PD(s)/PI(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 the Overall Core 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.

• All applications, regardless of the amount of direct costs requested for any one year, must address the following Resource Sharing Plans: Sharing Model Organisms.

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages. If required, the Data Management and Sharing (DMS) Plan must be provided in the Overall component.

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

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.
• In keeping with NIA’s strategic goal to enable and promote open science practices and FAIR (Findable, Accessible, Interoperable, and Reusable) data practices, and the NIA/NIH goal to enhance transparent reporting and increase research rigor and reproducibility, awardees must make all analytical methods, network models, and research tools available to the broad scientific community via the NIA-supported AD Knowledge Portal, NIH-designated data repositories, and/or open-source/open-access platforms.

Appendix:

Only 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.

PHS Human Subjects and Clinical Trials Information (Overall)

When involving human subjects research, clinical research, and/or NIH-defined 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

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). 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 in ASSIST, 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 Head 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 and Data Management Core leadership and explain the Core Head's specific roles and responsibilities in the management of the Center. The Administrative and Data Management Core will conduct oversight for the sharing of MPS models, methods, and data both within the center and with the external scientific community.

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 (e.g. AD Knowledge Portal, NIH-designated data repositories, and/or open-source/open-access platforms) as well as coordinate activities with the NIH Program Official. Clearly define the management plan for the Center, and how it will support achievement of the proposed goals and milestones. 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 infrastructure for rapid, open-access dissemination of data and methodology, and for rapid distribution of all tools and methods for their use by the scientific community. Indicate how the Core will enable the rapid and broad sharing of data and analytical outputs. 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.

Describe the Steering Committee. Include plans to convene this group. The committee should include the PD(s)/PI(s), Core heads, the NIA Project Scientist and the NIA Program Official. This committee will make the following key decisions: selection of candidate biomarkers to be used for characterization and validation of AD/ADRD MPS models; selection of standardized methods to enable rigorous preclinical therapeutic safety and efficacy testing; selection of projects for testing candidate therapeutics in AD/ADRD MPS models; selection of methods to increase scalability for rapid dissemination of models; and transparent reporting of research methodology and preclinical efficacy testing findings.

Describe the External Advisory Board. Include plans to appoint and convene this group of up to five members, from outside the Center, at least two times 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.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

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

Planned Enrollment Report: When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report: When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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)

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)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Bioinformatics and Computational Biology Core Head 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, specifically its role in bioinformatics for the creation of AD/ADRD 2D and 3D MPS models. Describe concisely the specific aims of the Core and explain how the Core will interact with the other cores of the Center. Describe plans to manage data in coordination with external data repositories (e.g., AD Knowledge Portal, NIH-designated data repositories, and/or open-source/open-access platforms).

Research Strategy: Indicate how the Core will collect, analyze, and integrate bioinformatics data from outside the Center (e.g., AD Knowledge Portal and/or other open-source/open-access platforms). Describe the strategies, methodologies, and computational analyses to be performed. Indicate how the Core will use current bioinformatics technologies to analyze MPS data (e.g., gene expression profiling, proteomic, immunohistochemical, metabolomic, morphological, biochemical analyses) to identify and validate translatable biomarkers that can assist in deep phenotyping of an AD-like disease progression in AD/ADRD 2D and 3D MPS models. Describe the strategies, methodologies, and analyses to be performed by the Core to integrate existing human bioinformatics data (e.g., by interfacing with existing NIA and NIH infrastructures for the purpose of cross validating biomarkers obtained from MPS bioinformatics). Indicate how the Core will coordinate data and methodology for rapid and open-access dissemination generated by the Center.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

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

Planned Enrollment Report: When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide

PHS 398 Cumulative Inclusion Enrollment Report: When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide

MPS Models Development and Validation 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 (MPS Models Development and Validation 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 (MPS Models Development and Validation Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (MPS Models Development and Validation 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) (MPS Models Development and Validation 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 (MPS Models Development and Validation Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of MPS Models Development and Validation Core Head 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 (MPS Models Development and Validation 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 (MPS Models Development and Validation Core)

Specific Aims: Describe concisely the plans of the proposed Core, specifically its role in creation of AD/ADRD 2D and 3D MPS models. Describe concisely the specific aims of the Core and explain how the component will interact with the other components of the Center.

Research Strategy: Describe each AD/ADRD MPS model project, including its testable hypothesis, as well as how each project will improve the translational validity of AD/ADRD models. Indicate how the Core will conduct extensive characterization and deep phenotyping of 2D and 3D MPS models. Indicate how the Core will develop and characterize translational biomarkers for the purpose of longitudinally characterizing AD/ADRD 2D and 3D MPS models. Specifically discuss how the Core will use current technologies (e.g., gene expression profiling, proteomic, immunohistochemical, metabolomic, morphological, biochemical analyses) using samples from human sources. Indicate how new models will be phenotypically characterized, including any new phenotyping technologies. Discuss how the Core will cross validate MPS biomarker endpoints with human data. Indicate how the Core will develop and validate translatable, pharmacodynamic biomarkers that can assess target engagement. Detail a plan for establishing iPSC cell lines and 2D/3D MPS models from individuals from diverse cohorts with various AD/ADRD phenotypes, including from individuals with specific naturally occurring mutations/risk alleles. Detail a plan to scale up the systems for use in AD/ADRD drug development.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

PHS Human Subjects and Clinical Trials Information (MPS Models Development and Validation Core)

Planned Enrollment Report: When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide

PHS 398 Cumulative Inclusion Enrollment Report: When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Preclinical Efficacy and Safety 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 (Preclinical Efficacy and Safety 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 (Preclinical Efficacy and Safety Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Preclinical Efficacy and Safety 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) (Preclinical Efficacy and Safety 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 ( Preclinical Efficacy and Safety Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Preclinical Efficacy and Safety Core Head 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 (Preclinical Efficacy and Safety 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 (Preclinical Efficacy and Safety Core)

Specific Aims: Describe concisely the plans of the proposed Core, specifically its role in testing candidate therapies in AD/ADRD MPS models. Describe concisely the specific aims of the Core and explain how the Core will interact with the other components of the Center.

Research Strategy: Describe how the Core investigators will develop and implement standardized best practices for the rigorous preclinical testing of AD/ADRD candidate therapeutics, including a core set of reporting standards. Describe the experimental approaches for testing candidate therapeutic agents, including the use of translatable pharmacodynamic (PD) biomarkers in evaluating therapeutic agents, as well as pharmacodynamic (PD)/pharmacokinetic (PK) and drug safety and toxicity approaches that may be required as part of evaluation of agents. Of special interest is the development of phenotypic screens that can be used to assess the ability of one or multiple compounds to normalize the activity of entire networks as therapeutic targets. Describe approaches to formal failure analysis of preclinical trials.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide

PHS Human Subjects and Clinical Trials Information (Preclinical Efficacy and Safety Core)

Planned Enrollment Report: When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide

PHS 398 Cumulative Inclusion Enrollment Report: When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 applications will be automatically assembled for review and funding consideration after submission, refer 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 How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. 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 form. 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 unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by NIA, 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 [email protected] when the application has been submitted. Please include the NOFO 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.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission 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 AD/ADRD MPS Translational 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.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project 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 project proposed).

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 project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project 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 to this NOFO:

• What is the likelihood that the project will achieve the overarching goals of the AD/ADRD MPS Translational Center to create, validate, and rapidly disseminate to all qualified researchers the AD/ADRD 2D and 3D MPS models?
• What is the likelihood that the project will have a positive impact on the direction of AD/ADRD research, specifically its impact on knowledge of basic etiology as well as preclinical and clinical therapy development and potential avenues for the treatment and prevention of the disease?
• How strong is the justification/rationale provided for potential translational benefit derived from the use of the proposed AD/ADRD MPS models?
• How well will the created disease models be able to recapitulate genomic, proteomic, metabolomic, and other biological indicators of AD/ADRD?
• How adequately d oes the application focus on critical gaps to address important questions or obstacles in AD/ADRD?
• How well w ill successful completion of the research aims promote the understanding of disease pathogenesis and advance the development of interventions?
• How comprehensive is the project team's plan for methods development to increase scalability for rapid dissemination of models and transparent reporting of research methodology and preclinical efficacy testing findings?
• How well d oes the Center demonstrate synergy among the Cores, such as how the Bioinformatics and Computational Biology Core and Preclinical Efficacy and Safety Cores will integrate and inform the MPS Models Development and Validation Disease Modeling Core, and how there will be multidirectional exchanges between the Cores?
• How cutting-edge i’s the science emanating from the Cores that will help design and create advanced and predictive AD/ADRD MPS models?
• How high is the potential for this research to assist in the creation of a preclinical pipeline of therapies that can be moved forward into clinical research and practice?
• How adequate are the Center's plans to maintain both an internal and an outward-facing publicly available website housing data generated by the Center?
• How adequate is the Center's plan to rapidly disseminate the MPS models and transparent reporting of research methodology and preclinical safety and efficacy testing findings to all qualified researchers?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? 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 to this NOFO:

• How adequate are the letter(s) of support from senior administration officials or other institutional officials from the PD(s)/PI(s)' institution(s)?
• How well d o the letters describe the level of institutional support for the Center including any leveraged funding or resources that may be provided by the institution(s)?

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?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? 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 project 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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

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 to this NOFO:

• How strong are the interactions between the components of the Center, including key personnel ?
• How essential i’s each component for addressing the overall goal of the Center?
• How adequate are the multi-directional exchanges between the Cores?
• How well w ill the Center/Cores interact with programs external to the Center?

Additional Review Criteria - Overall

As applicable for the project 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 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 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 Individuals Across the Lifespan

When the proposed project 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 individuals of all ages (including children and older adults) 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 Animals 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

As applicable for the project 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

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

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 Resource Sharing Plan(s) (e.g., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

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

As applicable for each individual Core, reviewers will provide an assessment of its strengths and weaknesses. The following items should be evaluated while determining scientific and technical merit, and in providing an overall impact score for the Core; however, separate scores will not be given for these items.

Review Criteria - Administrative and Data Management Core

• How concise are the plans of the proposed Administrative and Data Management Core leadership, including the Core Head's specific roles and responsibilities in the management of the Center?
• How sufficient is the oversight of the Administrative and Data Management Core for the sharing of MPS models, methods, and data both within the center and with the external scientific community?
• How adequate is multidisciplinary scientific leadership for the Center by PDs/PIs, who will have expertise in specific areas of research?
• How effective are the coordinate interactions and collaborations of the Cores and external programs (e.g. AD Knowledge Portal, NIH-designated data repositories, and/or open-source/open-access platforms) as well as coordinate activities with the NIH Program Official?
• How adequate is the management plan for the Center, including how it will support achievement of the proposed goals and milestones?
• How adequate are the plans for evaluation of progress across the Center and communication strategies to manage and track progress of the multiple Cores?
• How strong are the 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 by the scientific community?
• How well will the Core enable the rapid and broad sharing of data and analytical outputs?
• How adequate will the Core conduct oversight for these open-science activities?
• How adequate is the five-year timeline depicting Core goals, with milestones and detailed quantitative criteria by which milestone achievement will be assessed?

  Review Criteria - Bioinformatics and Computational Biology Core

  • How adequate are the concise plans of the proposed Core, specifically its role in bioinformatics for the creation of AD/ADRD 2D and 3D MPS models?
  • How well d o the specific aims of the Core concisely explain how the Core will interact with the other cores of the Center?
  • How adequate are the plans to manage data in coordination with external data repositories (e.g., AD Knowledge Portal, NIH-designated data repositories, and/or open-source/open-access platforms)?
  • How well will the Core collect, analyze, and integrate bioinformatics data from outside the Center (e.g., AD Knowledge Portal and/or other open-source/open-access platforms)?
  • How strong are the strategies, methodologies, and computational analyses to be performed?
  • How well will the Core use current bioinformatics technologies to analyze MPS data (e.g., gene expression profiling, proteomic, immunohistochemical, metabolomic, morphological, biochemical analyses) to identify and validate translatable biomarkers that can assist in deeply phenotyping of an AD-like disease progression in AD/ADRD 2D and 3D MPS models?
  • How adequate are the strategies, methodologies, and analyses to be performed by the Core to integrate existing human bioinformatics data (e.g., by interfacing with existing NIA and NIH infrastructures for the purpose of cross validating biomarkers obtained from MPS bioinformatics)?
  • How well will the Core coordinate data and methodology for rapid and open-access dissemination generated by the Center?

  Review Criteria - MPS Models Development and Validation Core

  • How adequate is the testable hypothesis for each AD/ADRD MPS model project , and how well will each project will improve the translational validity of AD/ADRD models?
  • How well will the Core Project conduct extensive characterization and deep phenotyping of 2D and 3D MPS models?
  • How adequately will the Core Project develop and characterize translational biomarkers for the purpose of longitudinally characterizing AD/ADRD 2D and 3D MPS models?
  • How well will the Core Project use current technologies (e.g., gene expression profiling, proteomic, immunohistochemical, metabolomic, morphological, biochemical analyses) using samples from human sources?
  • How strong are the plans for new models to be phenotypically characterized, including any new phenotyping technologies?
  • How adequately will the Core cross validate MPS biomarker endpoints with human data?
  • How well will the Core Project develop and validate translatable, pharmacodynamic biomarkers that can assess target engagement?
  • How strong is the plan for establishing iPSC cell lines and 2D/3D MPS models from individuals from diverse cohorts with various AD/ADRD phenotypes, including from individuals with specific naturally occurring mutations/risk alleles on?
  • How strong is the plan to scale up the systems for use in AD/ADRD drug development?

  Review Criteria - Preclinical Efficacy and Safety Core

  • How adequate are the concise plans of the proposed Core, specifically its role in testing candidate therapies in AD/ADRD MPS models?
  • How well d o the specific aims of the Core concisely explain how the Core will interact with the other components of the Center?
  • How well w ill the Core investigators develop and implement standardized best practices for the rigorous preclinical testing of AD/ADRD candidate therapeutics, including a core set of reporting standards?
  • How strong a the experimental approaches for testing candidate therapeutic agents, including the use of translatable pharmacodynamic (PD) biomarkers in evaluating therapeutic agents, as well as pharmacodynamic (PD)/pharmacokinetic (PK), and drug safety and toxicity approaches that may be required as part of evaluation of agents sufficient?
  • How adeuate are the plans for the development of phenotypic screens that can be used to assess the ability of one or multiple compounds to normalize the activity of entire networks as therapeutic targets?
  • How adequately described are the approaches to formal failure analysis of preclinical trials?

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIA, 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 will receive a written critique.

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.

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

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 NOFO. 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 2.4.4 Disposition of Applications.

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 recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. 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 NOFO 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.

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Prior Approval of Pilot Projects

Recipient-selected projects that involve {clinical trials or studies involving greater than minimal risk to human subjects} require prior approval by NIH prior to initiation.

• The recipient institution will comply with the NIH Guidance on Changes That Involve Human Subjects in Active Awards and That Will Require Prior NIH Approval.
• The recipient institution will provide NIH with specific plans for data and safety monitoring, and will notify the IRB and NIH of serious adverse events and unanticipated problems, consistent with NIH DSMP policies.

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, Recipients, and Activities, including of note, but not limited to:

• Federal-wide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS Assurance of Compliance form (HHS 690)) in which the recipient agrees, as a condition of receiving the grant, to administer programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity, The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. See https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

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 NOFO.

• For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.htmlandhttps://www.lep.gov.

• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• For guidance on administering programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/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.

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 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at 2 CFR Part 200, 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 recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

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

• Formation of a Steering Committee which will serve as the operational governing board. The Steering Committee should include: the PD(s)/PI(s), Unit leads, the NIH Project Scientist (voting), the NIH Program Official (ex officio) and external scientists (s) (if required).
• 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 collaboration with the NIA Project Scientist and other awardees.
• Determining experimental approaches and design protocols, setting project milestones, and conducting experiments.
• Participating in group activities, including Steering Committee, to share design and analysis techniques and promote comparability across studies wherever possible.
• Ensuring active participation of partner sites and collaborators in group activities, if applicable.
• Implementing Steering Committee recommendations for designing, implementing, evaluating, and disseminating Disease Modeling Projects, as appropriate and feasible.
• Adhering to the general NIA/NIH policies regarding sharing resources, data release, and resource sharing, as well as the specific data and resource-sharing policies proposed in the application, as modified by any negotiation prior to award.
• Adhering to NIA/NIH policies, including those regarding data release, intellectual property, and publications.
• Submitting periodic milestone reports in a standard format, as agreed upon by the Steering Committee.
• Attending and participating in Steering Committee meetings and accepting and implementing the guidelines and procedures, as appropriate.
• Implementing all scientific and policy decisions approved by NIA/NIH.
• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

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

An NIA Program Official will be assigned to the project and will be responsible for the normal scientific and 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. The Program Official will be responsible for assessing the progress of the project towards accomplishment of milestones, and for recommending the level of continued funding.

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 NIA Project Scientist will provide additional expertise that is needed for proper scientific management of the award. This includes assisting the PI/PD in enhancing the project's progress by providing access to various NIH resources, when appropriate, providing 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.

Areas of Joint Responsibility include:

Close interaction among the participating investigators will be required, as well as significant involvement from NIH, to develop appropriate strategies and tools to develop precision AD MPS models.

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 conference calls as needed to share information on data resources, methodologies, 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), the NIH Program Official (ex officio) 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 Steering Committee will:

• Participate in monitoring "day to day" scientific progress of the research project plan, assessing progress of the milestones.
• Review project proposals from the extramural community (academia/biotech/industry) to test candidate therapies in AD MPS models, decide on new projects, and develop a prioritized portfolio of therapeutic targets and drug candidates for testing.
• Convene video or audio teleconferences and yearly meetings to monitor progress on the research project plan, address issues or activities that impact the project, and identify areas of shared interest and potential for collaboration.
• Establish workgroups for specific tasks as needed, which could include representatives from the program and NIA.
• Meet at least annually with the External Advisory Board, or as dictated by the needs of the Project.

External Advisory Board: In consultation with NIA staff, an external board of advisors will be selected, to be comprised of individuals not directly involved in the Center to guide 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 units and Center participants.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: 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 recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described. If additional Data Management and Sharing requirements need to be added, please insert what requirements are desired.

All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

In keeping with NIA’s strategic goal to enable and promote open science practices and FAIR (Findable, Accessible, Interoperable, and Reusable) data practices, and the NIA/NIH goal to enhance transparent reporting and increase research rigor and reproducibility, recipient’s must make all analytical methods, network models, and research tools available to the broad scientific community via the NIA-supported AD Knowledge Portal, NIH-designated data repositories, and/or open-source/open-access platforms.

When multiple years are involved, recipients 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. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients 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 the threshold. 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 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, 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 75and 2 CFR Part 200 Award Term and Condition 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.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Zane Martin, Ph.D.
National Institute on Aging (NIA)
Phone: 301-827-7130
Email: [email protected]

Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-402-7700
Email: [email protected]

Jessica Perez
National Institute on Aging (NIA)
Telephone: 301-402-7739
Email: [email protected]

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.

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 and 2 CFR Part 200.