Part 1. Overview Information

Participating Organization(s)
National Institutes of Health (NIH)
 
Components of Participating Organizations

National Institute of Neurological Disorders and Stroke (NINDS)

National Heart, Lung and Blood Institute (NHLBI)

National Institute on Aging (NIA)

Funding Opportunity Title
Development and Validation of Advanced Mammalian Models for Alzheimer's Disease-Related Dementias (ADRD) (R61/R33 Clinical Trial Not Allowed)
Activity Code
R61/R33 Exploratory/Developmental  Phased Award
Announcement Type
New
Related Notices
None
Funding Opportunity Announcement (FOA) Number
PAR-19-167
Companion Funding Opportunity

None

Catalog of Federal Domestic Assistance (CFDA) Number(s)
93.853; 93.866; 93.837; 93.233; 93.838; 93.839
Funding Opportunity Purpose

This funding opportunity announcement (FOA) encourages research to develop, characterize and validate innovative mammalian models that recapitulate molecular, cellular, neuropathological, behavioral and cognitive hallmarks of the Alzheimer's Disease-Related Dementias (ADRD), including Lewy body dementia (LBD), vascular contributions to cognitive impairment and dementia (VCID), frontotemporal degeneration (FTD) and mixed etiology dementias (MED). Models will be expected to exhibit a broad range of features characteristic of the dementia disorder being modeled, including a mid- to late-life onset consistent with the human disorder, multiple age-dependent neuropathological processes and the associated behavioral, cognitive and/or physiological abnormalities. For each proposed mammalian model, a relevant suite of phenotypes that inform human ADRD disease progression and mechanisms should be characterized across the full life span or, for longer-living mammalian models, throughout the disease-relevant stages of adulthood. The goal of this FOA is to establish multi-dimensional mammalian models for ADRD to serve as tools to interrogate molecular disease mechanisms and identify therapeutic targets.

Key Dates

Posted Date

January 23, 2019

Open Date (Earliest Submission Date)
February 14, 2019
Letter of Intent Due Date(s)
February 14, 2019
Application Due Date(s)
March 14, 2019.

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

AIDS Application Due Date(s)
Not Applicable
 
Scientific Merit Review
June - July 2019
Advisory Council Review
August 2019
Earliest Start Date
September 2019
Expiration Date
March 15, 2019
Due Dates for E.O. 12372
Not Applicable
Required Application Instructions
It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.
  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
  3. Go to Grants.gov to download an application package to complete the application forms offline or create a Workspace to complete the forms online; submit your application to Grants.gov; and track your application in eRA Commons.
Learn more about the various submission options.

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

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

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.
  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

Alzheimer'sdisease-related dementias (ADRD) are a group of progressive, neurodegenerative disorders with mid- to late-life onset, including Lewy body dementia (LBD), vascular contributions to cognitive impairment and dementia (VCID), frontotemporal degeneration (FTD) and mixed etiology dementias (MED). Although the ADRD each have characteristic behavioral, cognitive and pathological features, symptomatic overlap and multiple neuropathological processes are common for these disorders, leading to substantial diagnostic challenges. Moreover, knowledge about the molecular pathobiology underlying these disorders remains incomplete, generating a major barrier to therapy development.

A variety of animal models, including mammalian models, have been developed to advance research into the molecular and cellular mechanisms of ADRD, to identify therapeutic targets, and to test therapeutic candidates. While existing ADRD animal models have enabled progress toward each of these objectives, those available to date do not recapitulate the full spectrum and complexity of the molecular, cellular, behavioral and cognitive pathology observed in typical dementias, including ADRD. In addition, existing animal models typically lack consideration of common comorbidities (e.g., cardiac disease, metabolic disorders including type II diabetes, sleep disorders, gastrointestinal dysfunction, immune dysfunction) as well as the influence of external exposures or insults (e.g., head trauma). Expert recommendations from the LBD, VCID, and FTD sessions at the Alzheimer’s Disease Related Dementias Summits (convened by the NINDS in 2013 and 2016 in response to the National Alzheimer’s Project Act), all emphasized the critical need for the development of new multi-dimensional animal models that successfully replicate combinations of co-occurring pathological characteristics of human dementias.

Purpose

The goal of this FOA is to encourage research to develop and comprehensively characterize multi-dimensional mammalian models designed to exhibit a broad range of features characteristic of human ADRD. Proposed models should show a mid- to late-life onset consistent with the disorder being modeled, multiple age-dependent and brain region-specific neuropathological processes and the associated behavioral, cognitive and/or physiological abnormalities. Although the proposed animal model is not required to reproduce every characteristic of the targeted ADRD, all models should be designed to develop more than one type of pathology (e.g., abnormal protein deposition, cerebrovascular disease, cerebral inflammation) that progresses with aging. Models that demonstrate a cognitive or behavioral phenotype reminiscent of the human ADRD are strongly encouraged. Genetic manipulations in the animal model should mimic the genetic component of the human disorder being modeled as closely as possible. The development of ADRD animal models with multiple genetic or other manipulations to model mixed brain pathologies and comorbidities is encouraged. For each proposed mammalian model, a relevant suite of phenotypes that inform human ADRD disease progression and mechanisms should be characterized across the full life span or, for longer-living mammalian models, throughout the disease-relevant stages of adulthood.

This FOA strongly encourages development of mammalian models that exhibit cerebral disease with one or more of the following brain pathologies: (i) Lewy bodies, (ii) tau pathology and/or beta-amyloid plaques, (iii) TDP-43-proteinopathy, (iv) vascular including cerebrovascular and cardiovascular, or (v) other relevant brain pathologies. Characterization of systemic disease and chronic comorbidities is in scope and is encouraged as scientifically relevant to the model.

Appropriate applications will propose to develop animal models that 1) are in mammalian organisms; 2) exhibit mid- to late-life onset with progression and 3) have, at a minimum, two brain pathologies, or, one brain pathology plus a common chronic comorbidity (e.g., cardiac disease, metabolic disorders including type II diabetes, sleep disorders, gastrointestinal dysfunction, immune dysfunction). Applications that do not meet these criteria will not be supported.

Examples of activities that are not appropriate for this FOA include, but are not limited to:

  • Any research involving human subjects
  • Research to develop, characterize and validate animal modelsin non-mammalian species
  • Research to characterize and validate previously developed mammalian models of ADRD

Phased Award Activities

The development, characterization and validation of mammalian animal models of human disease is inherently a multi-step process that includes initial feasibility testing followed bydetailed characterization and validation. Therefore, this funding opportunity will use a biphasic, milestone-driven R61/R33 mechanism. The R61 phase will support the development of the ADRD mammalian model and feasibility testing through initial characterization of salient phenotypes in an animal cohort of appropriate size. The R33 phase will support in-depth longitudinal characterization of neuropathology, physiology, genetics, behavior, cognition, and other relevant attributes that are essential components of the targeted ADRD as well as complete validation studies. Transition from the R61 to the R33 phase is contingent upon the successful completion of proposed milestones. The milestones should be clearly defined, quantifiable, and scientifically justified to allow the Program Director(s)/Principal Investigator(s) and Program Official assess progressinthe R61 phase.

Examples of activities for the R61 Phase include, but are not limited to:

  • Development of the mammalian model;applicants choosing to further develop an existing mammalian animal model (e.g., of a systemic, comorbid disease) into an ADRD model should fully characterize the model for any existing neuropathology (e.g., ischemic stroke, vascular disease, tau deposition)
  • Preliminary characterization of salient phenotypes in an animal cohort of appropriate size
  • Scale-up for characterization and validation studies in the R33 phase (breeding, aging, etc.)

Examples of milestones for transition from the R61 to the R33 phase:

  • Demonstration that the new animal model can be bred to sufficient cohort sizes to enable appropriately powered characterization and validation studies
  • Demonstration that the new mammalian animal model can survive to an age range that is relevant to the disease onset of the ADRD being modeled
  • Provision of preliminary evidence of age-related, human ADRD-relevant phenotypes in an appropriately sized cohort of animals and in both sexes
  • Provision of preliminary evidence that the new mammalian animal model is superior to existing and already available models for ADRD, or addresses a specific gap in modeling these disorders, and thus a rationale for transition to the R33 phase

Examples for activities in the R33 Phase include, but are not limited to:

  • Comprehensive, rigorous and appropriately powered characterization of relevant molecular, cellular, pathological, physiological, behavioral and/or cognitive phenotypes that inform human ADRD disease progression and mechanisms across the full life span or, for longer-living mammalian models, throughout the disease-relevant stages of adulthood and in both sexes
  • Rigorous and appropriately powered validation studies such as replication in a different animal cohort at the same site or at a different site, demonstration of similar responsiveness to pharmacological treatments, etc.

Additional Considerations: Applicants are strongly encouraged to contact Scientific/Research staff to discuss potential research projects prior to submitting an application.

NHLBI Interest Statement

The NHLBI supports research to understand the normal biological function of the heart, lung, blood and sleep (HLBS), as well as the pathobiological mechanisms important to the onset and progression of HLBS diseases. The NHLBI has shared interest with NINDS in VCID and is interested in applications proposing new VCID mammalian models that leverage known cardiovascular diseases and risk factors for dementia, either alone or in the presence of other AD/ADRD pathology and comorbidities such as sleep, blood, lung disorders, head trauma, and corresponding changes in the blood brain barrier. In addition, NHLBI is also interested in further characterization, optimization and repurposing of existing cerebrovascular and cardiovascular mammalian models to be used for VCID research.

Additional specific topics of interest include but are not limited to the following:

  • Determine the temporal sequence and causality of known cardiovascular risk factors for dementia in models of VCID, including the underlying biological processes, vascular changes, and the resulting brain pathologies and changes in cognitive function.
  • Characterize changes in cerebral vasculature and cognitive function in potential animal models for VCID that were originally designed as models of cardiovascular diseases and have well-documented phenotypes in peripheral vasculature and other organs, such as models for hypertension, small vessel disease, atherosclerosis, atrial fibrillation, and heart failure.
  • Characterize HLBS changes preceding cognitive impairment in animal models of VCID that have well-established phenotypes in the brain.
See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

Funding Instrument
Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed
New

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

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

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

NIH intends to commit up to $2,800,000 in FY 2019. NINDS intends to fund up to 4 awards, and NHLBI intends to fund up to 1 award.

Award Budget
Application budgets are not limited but need to reflect the actual needs of the proposed project.
Award Project Period

The project period for the R61 phase is limited to a maximum of 3 years. The project period for the R33 phase is limited to a maximum of 3 years. The entire award project period may not exceed 5 years total. Conversion to the R33 phase is contingent on completion of milestones in the R61 award period.

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations
Higher Education Institutions
  • Public/State Controlled Institutions of Higher Education
  • Private Institutions of Higher Education
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
  • 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)
Governments
  • State Governments
  • County Governments
  • City or Township Governments
  • Special District Governments
  • Indian/Native American Tribal Governments (Federally Recognized)
  • Indian/Native American Tribal Governments (Other than Federally Recognized)
  • Eligible Agencies of the Federal Government
  • U.S. Territory or Possession
Other
  • Independent School Districts
  • Public Housing Authorities/Indian Housing Authorities
  • Native American Tribal Organizations (other than Federally recognized tribal governments)
  • Faith-based or Community-based Organizations
  • Regional Organizations
  • Non-domestic (non-U.S.) Entities (Foreign Institutions)
Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed. 
Required Registrations
Applicant Organizations

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

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

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

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

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

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

Any individual(s), including collaborative teams, knowledgeable about ADRD pathobiology and experienced in the areas of behavioral phenotyping, neuropathology, experimental design and statistical analysis are encouraged to apply.

2. Cost Sharing

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

3. Additional Information on Eligibility

 
Applicant organizations may submit more than one application, provided that each application is scientifically distinct.
 
The NIH will not accept duplicate or highly overlapping applications under review at the same time.  This means that the NIH will not accept:
  • A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
  • A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
  • An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

Section IV. Application and Submission Information

1. Requesting an Application Package

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.
For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
 
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
  • Descriptive title of proposed activity
  • Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
  • Names of other key personnel
  • Participating institution(s)
  • Number and title of this funding opportunity

 
The letter of intent should be sent to:
 
Amelie Gubitz, PhD
Telephone: 301-496-5680
Fax: 301-480-1080
Email:gubitza@ninds.nih.gov

Page Limitations
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed
Instructions for Application Submission
The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.
SF424(R&R) Cover
All instructions in the SF424 (R&R) Application Guide must be followed.
SF424(R&R) Project/Performance Site Locations
All instructions in the SF424 (R&R) Application Guide must be followed.
SF424(R&R) Other Project Information
All instructions in the SF424 (R&R) Application Guide must be followed.
SF424(R&R) Senior/Key Person Profile
All instructions in the SF424 (R&R) Application Guide must be followed.
 
All instructions in the SF424 (R&R) Application Guide must be followed.
R&R Subaward Budget
All instructions in the SF424 (R&R) Application Guide must be followed.
PHS 398 Cover Page Supplement
All instructions in the SF424 (R&R) Application Guide must be followed.
PHS 398 Research Plan
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Research Strategy: Describe both the R61 phase and the R33 phase, including the R61 transitional milestones and overall timeline. The Research Strategy Section should be organized into sections on Significance, Innovation and Approach.

Significance: Include a brief description of the ADRD to be modeled and provide the rationale for developing the proposed new mammalian model(s) for this disorder, including the unmet need, limitations of existing models and potential advantages of the new model(s) to serve as advanced tools to interrogate molecular disease mechanisms and identify therapeutic targets.

Innovation: Describe the novel attributes of the proposed mammalian model, including their relevance to informing human ADRD disease progression and mechanisms. Discuss whether the concepts, approaches and methodologies to be used are innovative in the context of ADRD modeling.

Approach: Describe the overall strategy, methodology and other considerations that will be used to accomplish the Specific Aims of the R61 phase and the R33 phase, including 1) methods to characterize the animal model across its life span, or for longer-living mammalian models, throughout the disease-relevant stages of adulthood, and to evaluate how well it recapitulates features characteristic of the targeted ADRD, including age-dependent neuropathological processes and the associated behavioral, cognitive and/or physiologic abnormalities, as well as its genetic basis; 2) strategy for validating the animal model; 3) considerations of the potential to produce an animal model that will be feasible to implement and will meaningfully translate to human biology. Also address relevant biological variables, such as sex and age, and ADRD-related comorbidities, as applicable, and describe potential problems and alternative strategies.

Describe the roles of the investigators and collaborators, as applicable, in addressing the stated research objectives.

The application should adequately address issues of transparency and rigor, as described in the NIH guidance on rigor and reproducibility in grant applications: https://grants.nih.gov/reproducibility/index.htm and in related materials: https://www.ninds.nih.gov/Current-Research/Trans-Agency-Activities/RigorAndReproducibility

Milestones: Transition from the R61 to the R33 phase is contingent upon the successful completion of a set of proposed milestones. The specific milestones proposed in the application will depend on the goals of the application and the accomplishments necessary in the R61 phase for advancement into the characterization and validation studies proposed for the R33 phase. These milestones, with a timeline, are to be included as the last element of the Research Strategy section of the application and will be evaluated as part of the scientific and technical merit of the R61/R33 application. The milestones proposed in the application should be well-described, quantifiable, and scientifically justified to allow program staff to assess progress in the R61 phase. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. The clarity and completeness of the R61/R33 application with regard to specific goals and feasibility milestones are critical. Milestones should provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application as part of the consideration of the awarded project for further funding of non-competing award years by the Program Director(s)/Principal Investigator(s), and Program Official. 

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.
The following modifications also apply:
All applications are expected to include a Plan for Sharing of Model Organisms. Applicants are welcome to consider editing examples of such sharing plans, see https://grants.nih.gov/grants/policy/model_organism/, to include the sharing of any model developed with funding from this FOA. Awards made under this FOA will encourage that models be shared and distributed using appropriate standards and through deposition in an appropriate repository, if available. Project-specific details will be established at the time of award. Budgets should include sufficient resources to prepare and distribute the model.
Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
PHS Human Subjects and Clinical Trials Information
When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed.
Delayed Onset Study
All instructions in the SF424 (R&R) Application Guide must be followed.
PHS Assignment Request Form
All instructions in the SF424 (R&R) Application Guide must be followed.
 
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). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII. Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.
See more tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review NIH. Applications that are incomplete and/or non-compliant will not be reviewed.
Requests of $500,000 or more for direct costs in any year

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.
Post Submission Materials
Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.
Overall Impact
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).
Scored Review Criteria

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?

Does the project effectively address the goal of developing novel mammalian animal models that have the potential to serve as advanced tools to interrogate molecular disease mechanisms and identify therapeutic targets of ADRD? Is the rationale for developing the proposed new mammalian model(s) for the targeted ADRD, including the unmet need, limitations of existing models and potential advantages of the new model(s) strong?

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?

Are the investigators knowledgeable about ADRD pathobiology and experienced in the areas of behavioral phenotyping, neuropathology, experimental design, statistical analysis, etc., for the project? Are the roles of the investigators and collaborators, as applicable, in addressing the stated research objectives carefully defined in the research plan?

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?

Does the application include innovative concepts, approaches and/or methodologies to model ADRD?

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?
Have the investigators presented plans to characterize a relevant suite of phenotypes that inform human ADRD disease progression and mechanisms in the mammalian model across its life span or, for longer-living mammalian models, throughout the disease-relevant stages of adulthood?   Have methods for evaluating how well the mammalian model recapitulates features characteristic of the ADRD being modeled, including age-dependent neuropathological processes and the associated behavioral, cognitive and/or physiologic abnormalities, as well as its genetic basis, been systematically outlined in the application? Are the methods proposed to characterize the model appropriate for the ADRD being modeled? Is the strategy proposed for validating the model well-reasoned and appropriate? Have the investigators thoughtfully considered the potential to produce a mammalian model that will be feasible to implement and will meaningfully translate to human biology? 

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?

Additional Review Criteria
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.

Milestones and Timelines:

Are milestones robust and associated with clear, quantitative criteria for success that allow go/no-go decisions at the R61/R33 transition point? If a criterion is not to be used for go/no-go decisions, is it justifiable?

Does the set of milestones allow the evaluation of progress in the R61 phase and will successful completion of these milestones provide confidence that the investigator will be able to successfully implement the R33 phase?

Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without unnecessary steps? Are there additional key experiments that need to have milestones designated?

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 Children

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 Animal Section.

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations
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 following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3)  Genomic Data Sharing Plan (GDS).

 

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.

2. Review and Selection Process 

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), 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.
The review will be convened by the Center for Scientific Review.
  • May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
  • Will receive a written critique.
Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:
  • Scientific and technical merit of the proposed project as determined by scientific peer review.
  • Availability of funds.
  • Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

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

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency.  HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements.  FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award.  An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS.  The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.”  This provision will apply to all NIH grants and cooperative agreements except fellowships.
For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
Cooperative Agreement Terms and Conditions of Award
Not Applicable

3. Reporting

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.
A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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

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

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
Application Submission Contacts
eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov
 
GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267
Scientific/Research Contact(s)


Debra Babcock, MD, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9964
Email: dbabcock@ninds.nih.gov

Patrick Bellgowan, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1447
Email: patrick.frostbellgowan@nih.gov

Roderick Corriveau, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5680
Email: roderick.corriveau@nih.gov

Amelie Gubitz, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5680
Email: gubitza@ninds.nih.gov

Jue Chen, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0550
Email:jue.chen@nih.gov

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

Peer Review Contact(s)
Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).
Financial/Grants Management Contact(s)

Tijuanna E. DeCoster, PhD
National Institute of Neurological Disorders and Stroke (NINDS) 
Telephone: 301-496-9231 
Email: decostert@mail.nih.gov

Debbie Chen
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8023
Email: debbie.chen@nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Authority and Regulations
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.


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