Required Application Instructions

It is critical that applicants follow the 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.

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Background

Human genetic variants that favorably influence both longevity and development or progression of age-related chronic diseases have been identified. The number of such variants identified will likely increase in the near future. Ongoing additional analyses in a variety of population-based cohort studies and/or the use of new genomic platforms will likely clarify the presence or absence of significant relations between other variants and longevity. In addition, genomic findings related to life or health span in animal models or comparisons between humans and other species of varying life spans may suggest potential therapeutic targets for interventions that could favorably influence these outcomes in humans.

Therapeutic development based on target identification of genetic variants has been used successfully in other fields. For example, observations of the effects of loss-of-function PCSK9 variants on LDL cholesterol and other cardiovascular disease risk factors led to development of anti-PCSK9 antibodies for hypercholesterolemia. Similarly, novel potential therapeutic targets could be identified based on knowledge of functional pathways of gene variants associated with longevity. Because longevity is associated with diminished risk for a variety of diseases and conditions, targets identified through such strategies may be particularly valuable for protection against multiple age-related conditions, rather than just a single disorder.

An increasing variety of techniques for target identification based on genetic variation are being developed across academia, industry, and within NIH. The recent advent of novel high-throughput genomic tools and technologies, such as microarrays and next generation sequencing, has resulted in accumulation of genetic, genomic, and epigenetic information from population-based studies spanning a wide range of ages. Using such genetic and phenotypic information may elucidate relations between specific life span or health span-related variants and a variety of other phenotypes in order to identify pathways that may be associated with these variants. In addition, new biotechnology approaches, such as gene editing and use of iPS cell lines, may allow more rigorous and focused functional studies to aid in target identification.

Effective and coordinated use of these approaches requires collaboration among several diverse research fields that have rarely interacted in aging research. Such a multidisciplinary team could effectively leverage relevant cohort genetic data and perform integrated analyses in the selection and design of the most promising target identification and translation approaches. Expertise in strategies for applied research, such as those used in drug development, is also likely to be crucial. To date, no such team exists.

The present FOA requests applications proposing to establish a team that will conduct the planning activities necessary for the development of target identification strategies (described in the following section). The phrase "target identification strategy" refers to a concerted set of applied research approaches (e.g., additional analyses, conducting required types of studies/experiments and methodologies in the appropriate sequence) leading to the identification of genetic factors, pathways, or molecules by which activities could be favorably modified.

The proposed project should establish a collaborative research infrastructure with sufficient breadth of scientific expertise, staff time commitment, organizational structure, and operational procedures for information access, sharing, and decision-making to complete planning and evaluation of a number of potential target identification strategies within the five-year project period. The collaborative research infrastructure should consist of core expertise in genetics, genomics, epidemiology, aging research, translational genomics, drug development, statistics, and bioinformatics, and where appropriate, industry or other private sector liaisons. The infrastructure should also develop working relationships with individuals representing key information sources to facilitate data access and exchange, and to identify and utilize research resources and additional expertise available at the institutions of team members as needed for the project.

The U24 research infrastructure should address the four research objectives below. The relative degree of emphasis placed on specific aspects of these activities will depend on the variants selected and the amount of existing relevant information regarding them. A general principle underlying the sequence of these objectives is that intensive analyses of existing databases can inform the design of target identification strategies that require de-novo data collection.

1. Create an integrated data system with relevant data, informatics, and computational tools for assessing effects of gene variants.

This system should include data sets (or documented access to data sets) of human cohorts and/or families that allow analyses of relations of genetic variants to exceptional longevity and clinical outcomes. Awardees may use these data sets to clarify such relations already reported in the literature or to identify relations of additional new variants. However, new population or family studies on genetic factors influencing longevity involving de-novo data collection are outside the scope of this FOA.

In addition, awardees should evaluate integrating genomic and other -omics databases, other potentially relevant clinical data sets (e.g., from clinical trials of interventions that may influence potential targets), informatics resources, computational tools, and analytic techniques, with regard to their adequacy, value, and limitations for assessing the effects of genetic variants possibly related to human longevity on clinical outcomes and cell functions. For example, there are a number of database resources such as KEGG, BioPAX, Biomart, Gene Ontology (GO), Ingenuity IPA, Metacore and Genespring that enable integrated analyses of various omics data for understanding the biological underpinnings of the variant, identifying causal variants, and assessing the functional effects of genetic variants on downstream biological pathways. Other types of data that could be assessed include information from epidemiologic, clinical, physiologic, or other biologic studies, and results from high-throughput screening of compounds that might influence potential targets.

Based on this evaluation, awardees should select key databases, informatics resources, and computational tools, and incorporate them (linking them as needed) in a system for rapid and efficient exploration of potential functional biological and clinical effects of selected variants and of factors that regulate their expression or mediate their effects. The project should also establish a system for ongoing review of new relevant data, informatics, and methods arising from other sources over the course of the project.

Awardees may also develop novel tools to integrate epidemiologic, genetic, genomic, epigenetic, and proteomic data to reveal properties that cannot be ascertained from studies of individual components. This approach could involve, for example, combining high-throughput screening tools with computing and modeling tools to derive genomic convergence signals of aging and longevity, or pathway analysis on the identified targets to provide clues on relevant gene networks, biological pathways, and key molecules for potential therapeutic targets.

2. Evaluate the utility of gene variant(s) as prospective therapeutic target(s).

Variants strongly related to exceptional human longevity or health span should be evaluated fortheir potential utility as therapeutic target identification strategies through analyses using the system of databases and informatics/computational tools described in 1) above, and de-novo pilot studies.

Analyses of the databases could address topics such as effects of variants in regulatory regions on gene expression, effects on gene product function, effects on downstream factors influenced by the variant, relations of variants to clinical and physiologic phenotypes at different ages, or effects of drugs or other interventions on factors that may mediate the variants effects. For key issues that require new data collection, applicants may conduct small in vitro or in vivo pilot studies. Based on such analyses, awardees should evaluate the possible utility and feasibility of target identification strategies based on differing variants, taking into account such factors as current information, needs for additional studies, and the feasibility of conducting such studies, with regard to considerations such as:

• The magnitude of physiologic and clinical effects likely to result from mimicking effects of the variant.
• The full range of biologic functions and outcomes that could be affected favorably or adversely by modifying the expression of specific changes in activity of the gene product or of downstream factors influenced by it.
• Effects of existing drugs on factors in the same pathways as those influenced by the variant.
• The specific tissues in which the variant’s effects mediate its impact on health span and longevity, with particular consideration of druggability .
• Capabilities of current experimental or measurement technologies and methods to address key questions regarding the above considerations for which data are currently lacking.

3. Develop a strategic plan for experiments and analyses aimed at identification of one or more therapeutic target(s) for interventions that could potentially extend life span or health span.

For at least one possible variant whose potential as a basis for target identification strategies was evaluated as described in 2) above, applicants should develop a preliminary target identification strategy that specifies the sequence of studies to be done, and criteria for evaluating results from decisions about further studies in the strategy, discontinuation of the strategy, or the rationale for proceeding to additional steps.

Investigative methods that could be considered for inclusion in the planned strategy include:

• De-novo human physiologic studies on individuals with and without specific variants.
• In-vitro studies to characterize effects of variants on human cellular functions.
• Use of cellular engineering methods such as iPS cell generation or gene editing to clarify key pathways and tissues for targeting.
• In-vitro screening of small molecules for target effects.
• Evaluation of in-vitro or in-vivo effects of drugs currently in clinical use that may influence relevant targets.

This U24 will NOT support the actual implementation of the studies in the strategic plan, with the exception of small in-vivo or in-vitro pilot studies as needed for evaluating the feasibility and value of specific methods for this purpose. Support for the implementation of the studies in such a strategic plan may be requested in grant applications to other FOAs.

4. Establish a publicly-available research resource that provides access to and documentation for the computational and informatics tools used and developed in this project, and linkages to publicly-available databases for which they have been used.

This research resource should also provide documentation of scientific procedures developed and used by the collaborative team. The awardee should develop plans/options for long-term support and management of this research resource (i.e., beyond the project period), including the potential for interactive features to allow incorporation of new information by other investigators.

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

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) are not 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.

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

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from 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.

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

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).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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.

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:

Nalini Raghavachari, PhD
National Institute on Aging (NIA)
7201 Wisconsin Avenue, Suite 3C307
Bethesda MD 20892-9205
(ZIP 20814 for Fed Ex)
Email: Nalini.raghavachari@nih.gov
Telephone: 301-435-3048
Fax: 301-402-1784

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 FOA.

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.

Facilities and Other Resources: Describe what access the team has to relevant cohort data and other data sets proposed for inclusion, if not publicly available.

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

Biographical Sketch: The description of the role of senior personnel in the biosketch should focus on how the individual's expertise contributes to the interdisciplinary goals of the application and provide evidence of interdisciplinary collaborative efforts.

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

Application budgets should include costs for convening up to three, in-person meetings per year in the Washington, DC area. These meetings may involve study-wide meetings, members of the Steering Committee, External Monitoring Board (if one is formed), and NIA staff.

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:

Specific Aims: The application should describe the specific aims of the project in relation to this FOA’s four principal goals, which are described in detail under Research Objectives in Section I of the FOA.

Research Strategy:

Approach

The application should describe the specific approach to be taken for each of the FOA’s four research objectives, with particular regard to the following aspects:

1) Creation of an integrated database system of relevant data, and informatics and computational tools. Applicants should identify specific data resources to be considered for inclusion in the system, including key genomic and population databases and informatics resources. The applicant should describe how assessment of the value and limitations (e.g., data quality) of the above data resources would be performed, including statistical considerations where appropriate. The application should indicate the criteria to be used in selecting components to be included in the system, and a preliminary plan for ways in which they might be integrated and used in the analyses described in 2) below. Applicants should identify needs for development of additional informatics resources and computational tools for the system and how they would meet these needs. The applicants should describe and document agreements for use of databases that are not publicly accessible. The applicants should describe methods for updating the system by inclusion of new data, computational tools or informatics resources that may become available over the course of the project.

2) Variants with strong evidence of relation to increased human longevity or enhanced health span should be evaluated for their potential utility as a basis for developing therapeutic target-identification strategies. This objective may be achieved through analyses using the system of databases and informatics/ computational tools described in 1) above, and de-novo pilot studies. The applicants should describe the evidentiary criteria used to select the variants proposed for this evaluation and how specific proposed variants for evaluation meet these criteria. The application should also describe the criteria to be used to evaluate the selected variants with regard to their potential utility as a basis for developing therapeutic target ID strategies, the types of data to be analyzed, and the analytic/informatics/computational approaches (including statistical methods) that will be used. Applicants should describe briefly the design and analytic methods for any proposed in vitro or in vivo pilot studies involving new data collection.

3) Based on evaluations as described in 2) above, develop a strategic plan for experiments and analyses aimed at identification of one or more therapeutic target(s) for interventions with the potential to extend life span or health span. Since the analyses to inform the evaluation and selection of specific variants on which to base plans for target identification strategies will not have been conducted at the time of application, the applicant is not expected to provide a specific plan of studies aimed at target identification based on any given variant. However, applicants should describe the methods for target identification in which they have expertise (e.g., in vitro functional studies, high-throughput small molecular screening) and discuss general approaches and the basis for selecting a strategic sequence of studies to clarify the effects of favorable variants on cell and tissue function, the molecules or pathways that mediate these effects, and the effects of modulating the activity of these molecules or pathways. Applicants should also describe approaches for setting benchmark criteria based on critical studies that clarify the utility of further target-identification efforts focused on a particular variant or pathway.

4) Establish a publicly available research resource providing access to and documentation of the computational and informatics tools developed and used in this project, and linkages to publicly-available databases for which they have been used. The application should include a timeline for establishing the resource before the end of the award period. Applicants should describe approaches to providing sufficient documentation on the contents of the resource and methods for its use, including computational and informatics methods developed by the study team, and plans and options for long-term support and management of this research resource (i.e., beyond the project period).

Though conduct of small pilot de-novo studies to clarify prospects for potential strategies (e.g., to explore functional pathways associated with potential targets, or effects of existing drugs affecting such pathways) may be included in the activities, implementation of the target-identification strategies to be developed, beyond pilot studies or exploratory data analysis, is outside the scope of this FOA.

External Monitoring Board: Applicants may elect to have an External Monitoring Board that can provide guidance as needed to the PD(s)/PI(s), with subject-matter expertise to supplement or complement the core areas of expertise required for the multidisciplinary team. This information should be included in the Approach section of the Research Strategy. The application should identify the expertise appropriate for the monitoring board and the number of members. Applications should NOT specify the names of individuals or provide biographical sketches of proposed monitoring board members.

Operational procedures

The applicant should describe the organizational and operational procedures of the collaborative research infrastructure and how the expertise of the members will be integrated and applied to complete planning and preliminary evaluation of a number of potential target identification strategies within the project period. Plans for documentation of key procedures should also be included.

Letters of Support: The application should include letter(s) of support from partnering organization(s), if any, and for demonstrating access to any databases or other resources proposed for use as outlined in the application.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide with the following modifications:

• The application should include plans for sharing of data and any unique research resources that are generated by the project in concordance with NIH policies on the sharing of data and resources. It is expected that resources developed by the project will be made available to the broader scientific community.
• The applicant should describe how publicly-available data will be shared for downstream analyses. .
• The applicant should provide details for establishing the publicly available research resource on prospective therapeutic targets with all the clinical, genotypic and phenotypic information to be included.
• Mechanism for distribution and access of this database to/by the scientific community should also be included in the application.

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

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

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

Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

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 Applying Electronically.

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 valid PD(s)/PI(s) 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 by the Center for Scientific Review and responsiveness by the National Institute on Aging. Applications that are incomplete and/or nonresponsive will not be reviewed.

In order to expedite review, applicants are requested to notify the NIA Scientific Review Branch by email at VemuriR@nia.nih.gov when the application has been submitted. Please include the FOA number and title, PD(s)/PI(s) name(s), and title of the application.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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

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

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? 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 New Investigators, or 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? 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?

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 children, justified in terms of the scientific goals and research strategy proposed?

In addition:

Are the proposed organizational and operational procedures of the research infrastructure feasible and effective to achieve the goals of the project within the five-year project period?

Re FOA Research Objective 1: How likely is the plan for creation of an integrated database system, and informatics and computational tools, to become an effective system for evaluation of potential target identification strategies? Has the applicant described in sufficient detail the components considered for inclusion, and methods for assessing data quality? Are the proposed methods for updating the system adequate?

Re FOA Research Objective 2: Are the plans for using the database system to evaluate the potential utility of variants for target identification adequate? Are the proposed criteria for selecting variants for this evaluation appropriate? For the selected variants, are the criteria for evaluating their potential utility as a basis for developing therapeutic target ID strategies appropriate? Are the proposed analyses of the databases well-designed? If de-novo pilot studies are proposed, are their contributions to target identification clearly explained, and are their design and statistical methods adequate?

Re FOA Research Objective 3: Are the general approaches to develop target identification strategic plans based on promising variant(s) adequate? Is the range of potential approaches (e.g., in vitro functional studies, additional phenotyping, additional sequencing, high-throughput screening) sufficiently broad, and are the bases on which they would be selected well-justified? Are the potential limitations of these approaches and possible alternative strategies adequately addressed? Are the approaches for setting benchmark criteria appropriate for informing decisions about continuing further target identification efforts on a particular variant or pathway?

Re FOA Research Objective 4: Are plans reasonable and described in adequate detail with regard to establishing and managing the publicly available research resource data, computational/informatics tools, provision of adequate documentation to facilitate public use, and options for long-term support?

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?

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 six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

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

Inclusion of Women, Minorities, and Children

When the proposed 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 children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. 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

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

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

Not Applicable

Select Agent Research

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

Resource Sharing Plans

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

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.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the 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:

• 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 scores.
• Will receive a written critique.
• Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

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

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

After the peer review of the application is completed, the PD(s)/PI(s) will be able to access his or her Summary Statement (written critique) via the eRA Commons.

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

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.

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.

Cooperative Agreement Terms and Conditions of Award

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 Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

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

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

• The PD(s)/PI(s) will have the primary responsibility for carrying out the planning, organizing and implementation of research activities, day-to-day administrative functions and overall development of the U24 program.
• The PD(s)/PI(s) should establish a Steering Committee (SC) to oversee the activities of the collaborative research team.
• Awardees 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:

• The NIA Project Scientist will serve as the contact point for all facets of the scientific interaction with the awardee(s). The NIA Project Scientist may also participate in data analyses, interpretations and ensure the public availability of data, findings and related resources developed during the course of the U24 project. The NIA Project Scientist will serve on the Steering Committee and also be responsible for attendance at meetings of the SC.
• The NIA Project Scientist may serve as co-author in publications as appropriate (dependent on the extent of involvement in the study) and jointly agreed through the SC..
• NIA will designate additional NIA staff as a program official to provide advice to the awardee on administrative issues and will perform the normal stewardship functions of the award.
• The application must also include a statement indicating the applicant’s willingness to abide by the Cooperative Agreement Terms and Conditions of the Award.
• Awardees 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.

Areas of Joint Responsibility:

• The Steering Committee (SC) will serve as the governing body for the U24 project. It consists of the PD(s)/PI(s) of the U24 and NIA staff (one voting member). The SC will act collectively to approve planned analyses and/or pilot studies, establish study policies, help resolve issues and policy decisions, and provide direction and guidance to the project. The SC will also act as liaisons to potential industry collaborators, and fill other roles as defined by the project. The SC will meet regularly via teleconferences and periodically have in-person meetings.

Dispute Resolution:

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

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

A final progress report, 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.

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
Email: GrantsInfo@nih.gov

Nalini Raghavachari, PhD
National Institute on Aging
Telephone: 301-435-3048
Email: nalini.raghavachari@nih.gov

Ramesh Vemuri, Ph.D.
National Institute on Aging
Telephone: 301-496-9666
Email: VemuriR@nia.nih.gov

Linda Whipp
National Institute of Aging
Telephone: 301-402-7731
Email: whippl@mail.nih.gov

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 Parts 74 and 92.