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 Funding Opportunity Announcement.

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 NOFO or in a Notice from 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

Background

AD/ADRD exhibit high heritability with a complex genetic architecture. However, the known risk factors do not provide a complete account for AD cases, suggesting missing heritability yet to be identified. A recent large meta-analysis of 2,748 twin studies found that the contribution of environment across thousands of complex human phenotypes was nearly equal to that of genetics. Epidemiologic studies have demonstrated the association of environmental factors with neurodegeneration and AD/ADRD. A study assessing organophosphate exposure in a cohort of aging Mexican Americans found significantly increased dementia risk and cognitive decline in elderly Hispanics. Studies in both human and animal models have shown that poor diet, obesity, chronic stress, and exposure to heavy metals worsen pathogenetic effects of APOE4. In transgenic mouse models carrying APOE4, air pollution increases amyloid deposition. Animal studies have revealed that heavy metals such as lead and cadmium induce elevated brain levels of amyloid-β protein precursor, amyloid-β and tau, and altered learning and memory behaviors. Despite ample evidence from animal studies, evidence in humans supporting these associations is very limited. Mechanistic studies on biological processes leading to clinically relevant disease outcomes are lacking. The importance and specific nature of GxE interactions on brain aging and AD/ADRD are largely unexplored.

Studying GxE interactions may lead to the identification of novel risk variants and genetic contributors that act through the interaction but only have marginal effects, shedding light on missing heritability of AD/ADRD. Delineating the functional outcome of GxE interactions holds great potential to reveal novel disease mechanisms and help understand the nature of AD heterogeneity. Such findings may in turn enhance opportunities for translation to personalized prevention and therapeutic intervention. To date, few studies have examined the complex interplay of genetic and environmental factors and its influence on brain aging and AD/ADRD. The wide range of environmental factors and complex realities of environmental exposures pose challenges to such studies. Limited sample size and insufficient statistical power hamper the detection of specific GxE interactions, especially when the interactions have small effect sizes. Human cell-based in vitro and ex vivo models offer an alternative approach that complements animal models to overcome the limitations of human studies. The emergence of the direct reprogramming technology holds even greater promise for better modelling aging-related diseases and environment influence as directly reprogrammed neurons preserve epigenetic signatures of aging and environment-induced signatures better than induced pluripotent stem cells (iPSCs)-derived neurons. Combining innovative human cell-based systems with genome editing technology enables a rapid, less expensive, and scalable strategy to investigate how the genome interacts with the exposome across different cell types of the human brain. Such studies have the potential to improve our understanding of the impact of environmental exposures on gene regulation, molecular pathways, cellular functions, and disease etiology; thus, building a foundation for novel preventative and therapeutic strategies for AD/ADRD.

Purpose

This NOFO invites applications that propose interdisciplinary research projects that utilize disease relevant human cell-based in vitro and ex vivo models to characterize the effects of GxE interactions on gene regulation and cellular functions, and to elucidate toxicant mediated molecular and cellular mechanisms in brain aging and AD/ADRD. Collaborations between neuroscience researchers and environmental health scientists are strongly encouraged.

Research Objectives

The objective of this initiative is to stimulate research to gain mechanistic insights into GxE interactions in response to environmental toxicants using human cell-based models.

Applicants are encouraged to propose research that incorporates biological and genetic information from population-based studies to provide insights into the interaction of genetic variations and toxicants and how these interactions contribute to risk and outcomes of neurodegeneration and AD/ADRD.

Environmental exposures of primary interests include the following:

• Industrial and agricultural chemicals
• Metals
• Pollutants
• Other well-characterized toxicants

Human cell based in vitro & ex vivo models of primary interests include the following:

• Minimally transformed human cells from patients
• iPSCs derived from patients, panels of isogenic iPSCs, three-dimensional iPSC-derived or adult stem cells (AdSCs)-derived organoid culture systems
• Directly reprogrammed cells and induced cell organoids
• Tissue/organ-on-a-chip platforms, microfluidics platforms, and other emerging innovative co-culture systems that recapitulate the hallmarks of AD/ADRD and in vivo physiological conditions
• In vivo chimeric models with human iPSC-derived brain cells transplanted into appropriately selected animal models

Specific research areas that are of great interest are the following:

• Systematically interrogate genetically different and disease relevant human cell-based in vitro and ex vivo models with well characterized environmental toxicants such as chemicals, metals, pollutants
• Identify genetic risk and/or protective factors responding to environmental toxicants. Dissect the functional role of genetic variants interacting with environmental perturbations and delineate the causal pathways underlying the heterogeneity of AD/ADRD
• Identify regulatory variants and genomic elements mediated by toxicants that modulate gene expression and epigenetic alterations. Regulatory genomic elements may include noncoding variants, noncoding RNAs, retrotransposons and other classes of transposable elements
• Evaluate multi-omic molecular profiles and phenotypic outcomes resulted from environmental perturbations. Elucidate tissue and/or cell type specificity, composition of molecular signatures, and the role of sex or ethnicity differences in phenotypes influenced by toxicants
• Characterize and validate the effects of GxE interactions on molecular pathways, cellular functions, and disease pathophysiological processes such as pathogenic protein aggregation, oxidative stress, mitochondrial dysfunction, and neuroinflammation
• Uncover molecular and cellular mechanistic underpinnings and biological plausibility of toxicants on neurodegeneration and pathogenesis of AD/ADRD
• Integrate GxE interactions into Polygenic Risk Score (PRS) to improve diagnosis and treatment response for AD/ADRD
• Validate or further characterize existing GxE findings. Validation studies may include in vivo animal models to replicate or confirm in vitro/ex vivo functional endpoints and readouts

Non-Responsiveness Criteria (Applications Not Responsive to this NOFO)

The following types of applications will be considered non-responsive and will be withdrawn prior to review:

• Applications that are primarily oriented on computational analyses and/or modeling of existing data sets with limited effort on experimental approaches
• Applications that primarily focus on development of new in vitro tissue or organotypic culture systems
• Applications that primarily focus on multi-omics profiling with limited effort on studying the impact of GxE on brain aging or AD/ADRD

Consortium and Annual Investigator Meetings

This NOFO, in conjunction with its two companion NOFOs: RFA-AG-24-022 and RFA-AG-24-023, aims to establish a Precision Environmental Health in AD/ADRD Tri-consortium and lay the foundation for a precision environmental health approach to AD/ADRD risk reduction and disease prevention.

This initiative will operate under open-science principles: all data and analytical outputs will be shared rapidly and broadly via the NIA-supported AD Knowledge Portal. iPSC lines will be shared via NIA-funded National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD). Investigators under this consortium must participate in an annual Program Director/Principal Investigator (PD/PI) meeting. The annual meeting will provide a forum for investigators to discuss research updates, identify opportunities for synergy and collaboration across projects (e.g., data harmonization, protocol optimization), and identify pertinent research challenges and solutions.

Applicants should include funds to support travel to the meeting in their yearly budget.

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 Government

• 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)

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.

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.

• 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 their 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.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per 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 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, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. 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 notice of funding opportunity 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.

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 NIA 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:

Alison Yao, Ph.D.
National Institute on Aging (NIA)
Division of Neuroscience (DN)
Telephone: 301-827-7264
Email: [email protected]

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

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this NOFO.

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

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

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

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

The PD(s)/PI(s) should have demonstrated accomplishment in effectively leading multidisciplinary teams. If the application is multi-PD/PI, investigators should have complementary and integrated expertise and skills in order to provide an appropriate leadership approach, governance, plans for conflict resolution, and organizational structure applicable to the study. The applicant(s) should have experience overseeing selection and management of sub awards, if needed.

R&R or Modular Budget

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

PIs, and other key staff members, must attend the Precision Environmental Health in AD/ADRD Tri-Consortium annual meeting. The meeting will be in-person, and will be held in the Bethesda, Maryland area. The meeting is expected to last for two days. Applicants should include funds to support travel to the meeting in their budget.

R&R Subaward Budget

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

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

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

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.

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.

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 Findable, Accessible, Interoperable, and Reusable (FAIR) data practices, and the NIA/NIH goal to enhance transparent reporting and increase research rigor and reproducibility, recipients must make all data, analytical methods, and research tools available to the broad scientific community via the NIA-supported AD Knowledge Portal, or through other NIH-designated data repositories, and/or open-source/open-access platforms adopting the FAIR principles.

To this end:

• All data sets used/generated on the project (such as data about phenotypes and high-dimensional omic data, including genomic, proteomic, and metabolomic data generated from cell-based and animal models) will be made accessible and reusable by qualified individuals other than the original data generators to enable multiple parallel approaches to data analysis and interpretation.
• All analytical methodologies will be made fully reproducible and transparent so that results can be vetted and existing analysis techniques can be quickly applied to new application areas.
• All models of biological systems and networks will be openly available to users such that theoretical predictions can be rapidly validated experimentally.
• All disease models generated in the course of the project will be made freely available to qualified investigators to accelerate their characterization, validation, and translational utility.
• All biological samples used to generate data with this award will be made available to all recipients of this initiative and to other qualified investigators.

Recipients will be expected to have all data and analytical results deposited in the AD Knowledge Portal and/or other NIH-designated repositories after they have undergone basic quality control (within 3 months of data generation completion). Data and analytical results/tools shared via the AD Knowledge Portal will be made broadly available twice a year and no later than 6 months after deposition. Data will be accessible via open or controlled access, depending on the data type and source and as determined by the informed consent documents for each study guided by the local Institutional Review Board (IRB). There will be no publication embargo imposed on the use of data after they have been made available through the AD Knowledge Portal or other data repositories.

iPSC lines will be shared via NCRAD.

Applications must provide a plan and timeline for data generation, tools development, data and biospeciman reporting and deposition as part of a complete Data Management and Sharing Plan. Program staff may negotiate modifications to the plan prior to funding.

Applicants should include appropriate support for annotation and curation of the molecular and phenotype data used and/or generated on the project to maximize the usability of the data by the broader research community.

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

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

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.

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

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

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.

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.

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 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) 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. See Section III of this NOFO for information on registration requirements.

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.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by the National Institute on Aging, 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.

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.

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?

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?

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?

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.

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.

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) (i.e., 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.

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.
• Compliance with open-science, open-source principles and adherence to NIH guidelines for rigorous study design and transparent reporting, in compliance with NIH guidance on rigor and reproducibility.

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 recipient's business official.

Recipients 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 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: Recipient 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.

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

• Federal wide Research Terms and Conditions
• 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 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.html and https://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 (DHHS) grant administration regulations at 45 CFR Part 75 and 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 the NIH as defined below.

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

Defining the details for the projects within the guidelines of this NOFO. The PD/PI will agree to accept the close coordination, cooperation, and participation of the NIH staff (Project Scientists) in those aspects of scientific and technical management of the projects as described below.

Specifically, the PD/PI(s) supported by this initiative will:

• Retain the primary authority and responsibility for the project as a whole, develop the methods and procedures to accomplish the aims and objectives of the NOFO, and prepare publications.
• Provide, in addition to standard annual progress reports (see Section VI.4. Reporting), progress on annual milestone and other relevant information to the NIH Project Scientist(s) or Program Officer, and coordinate and cooperate with NIH staff and other members of appropriate collaborating NIH programs.
• Work directly with the NIH Project Scientist(s) on the coordination of intra-program activities and the integration of individual projects within the Impact of 'Precision Environmental Health in AD/ADRD Tri-Consortium,' as well as with other relevant NIH programs.
• Join the Precision Environmental Health in AD/ADRD Tri-Consortium, attend the annual Tri-Consortium meeting in-person, and budget for travel to physically attend the Tri-Consortium meeting, along with other critical staff.
• Participate in the appropriate coordinating meetings and/or working groups, and/or teleconferences as needed.
• Agree not to disclose confidential information obtained from other members of the Precision Environmental Health in AD/ADRD Tri-Consortium and extended research network.
• 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 DHHS, PHS, and NIH policies.

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

One or more designated NIH Program Staff members, acting as Project Scientists, will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards. The role of the Project Scientist(s) will be to facilitate and not to direct.

Specifically, the NIH Project Scientist will:

• Provide technical assistance and advice to the recipient as appropriate to achieve the aims of the cooperative agreement.
• Work directly with the recipient to facilitate their interactions within the Precision Environmental Health in AD/ADRD Tri-Consortium.
• Promote and help coordinate collaborative efforts that involve interactions with other members of the AD translational research community, as well as with other NIH-sponsored programs, projects, and centers where appropriate.
• Assist in the interaction between the recipient and investigators at other institutions, as appropriate for the program.
• Assist in avoiding unwarranted duplication of effort.
• The NIH Project Scientist(s) may form an External Scientific Panel (ESP) composed of senior non-federal scientists who are not directly involved in the activities of the Precision Environmental Health in AD/ADRD Tri-Consortium. The ESP will provide feedback to NIH on the progress of the Precision Environmental Health in AD/ADRD Tri-Consortium milestone deliverables, on the contributions of individual projects and/or project collaborations within the consortium, and on the progress and effectiveness of the consortium as a whole.

To help carry out these duties, Project Scientists may consult with non-NIH experts in the field.

The NIH Project Scientist(s) will perform the initial analysis of recipient milestones and will work with the Program Officer on any milestone renegotiations.

Additionally, an NIH Program Officer will be responsible for the normal scientific and programmatic stewardship of the awards and will be named in the award notice. In addition, the NIH Program Officer will have the option to recommend, following consultation with the NIH Project Scientists(s) the withholding or reduction of support from any project that substantially fails to achieve its goals according to the milestones agreed to at the time of the award.

NIH reserves the right to withhold funding or curtail an award in the event of substantive changes in the project, or failure to make sufficient progress toward the scope with which NIH concurred, or ethical or conflict of interest issues.

Areas of Joint Responsibility:

The NIH Project Scientist(s) and the PDs/PIs of the Precision Environmental Health in AD/ADRD Tri-Consortium will be jointly responsible for the coordination of intra-program activities and the integration of individual projects with other appropriate NIA and NIH programs. Joint responsibilities include:

• Developing working groups and/or coordinating committees and trans-project efforts, as needed.
• Organizing workshops to promote outreach.
• Convene to assess progress, discuss data resources, establish priorities, consider policy recommendations, propose publication guidelines and discuss strategies.
• Meet in-person, virtually, or by teleconference, with additional project staff and/or NIH staff, on a schedule to be determined.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual 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 DHHS 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.

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 data practices, and the NIA/NIH goal to enhance transparent reporting and increase research rigor and reproducibility, recipients must make all data, analytical methods, and research tools available to the broad scientific community via the NIA-supported AD Knowledge Portal, or through other NIH-designated data repositories, and/or open-source/open-access platforms adopting the FAIR principles.

To this end:

• All data sets used/generated on the project (such as data about phenotypes and high-dimensional omic data, including genomic, proteomic, and metabolomic data generated from cell-based and animal models) will be made accessible and reusable by qualified individuals other than the original data generators to enable multiple parallel approaches to data analysis and interpretation.
• All analytical methodologies will be made fully reproducible and transparent so that results can be vetted and existing analysis techniques can be quickly applied to new application areas.
• All models of biological systems and networks will be openly available to users such that theoretical predictions can be rapidly validated experimentally.
• All disease models generated in the course of the project will be made freely available to qualified investigators to accelerate their characterization, validation, and translational utility.
• All biological samples used to generate data with this award will be made available to all recipients of this initiative and to other qualified investigators.

Recipients will be expected to have all data and analytical results deposited in the AD Knowledge Portal and/or other NIH-designated repositories after they have undergone basic quality control (within 3 months of data generation completion). Data and analytical results/tools shared via the AD Knowledge Portal will be made broadly available twice a year and no later than 6 months after deposition. Data will be accessible via open or controlled access, depending on the data type and source and as determined by the informed consent documents for each study guided by the local Institutional Review Board (IRB). There will be no publication embargo imposed on the use of data after they have been made available through the AD Knowledge Portal or other data repositories.

iPSC lines will be shared via NIA-funded NCRAD.

Applications must provide a plan and timeline for data generation, tools development, data and biospecimen reporting and deposition as part of a complete Data Management and Sharing Plan. Program staff may negotiate modifications to the plan prior to funding.

Applicants should include appropriate support for annotation and curation of the molecular and phenotype data used and/or generated on the project to maximize the usability of the data by the broader research community.

4. Reporting

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 $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.

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]

Alison Yao, Ph.D.
National Institute on Aging (NIA)
Division of Neuroscience (DN)
Telephone: 301-827-7264
Email: [email protected]

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

Jeni Smits
National Institute on Aging (NIA)
Telephone: 301-827-4020
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.