It is critical that applicants follow the instructions in the Research Instructions for 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

For the purposes of this FOA, resilience is defined as the dynamic ability to maintain or recover appropriate function in response to a stressor. With advancing age, the prevalence of impairments in many of these responses increases. Although there has been considerable aging research on social and psychologic factors influencing responses to a variety of stressors, our understanding of age-related changes in responses to physical stressors has significantly lagged behind. Furthermore, responses to a specific physical stressor or a combination of stressors can also be diverse and differ across individuals. Thus it is useful to consider specific resiliencies, rather than a global concept of resilience. Examples of specific resiliencies include:

• Recovery of ambulation after hip fracture
• Healing of soft-tissue musculoskeletal injury
• Successful fracture union
• Healing of incisional wounds
• Recovery of hematopoietic function after cancer chemotherapy
• Maintenance of cardiovascular function after major surgery
• Maintenance or recovery of skeletal muscle function after immobilization or bed rest
• Maintenance or recovery of cognitive function following major illness or surgery, or exposure to general anesthesia, chemotherapy, or other agents

Several of the elements needed for incisive human studies on many resiliencies remain undeveloped. In particular, a thorough and precise phenotypic framework to characterize most resiliencies has not been developed. In addition, for responses to unpredictable stressors, there are substantial challenges in obtaining information on persons status before the stressor and immediately following it (e.g., in critical care settings). To facilitate research progress leading to interventions to maintain or improve specific resiliencies across the life span, there is a fundamental need for more precise operational definitions, diagnostic and predictive tests, and an understanding of the physiologic/molecular mechanisms underlying responses to different physical stressors.

Characteristics of an effective test of resilience include a well-defined, quantifiable stressor; a reliably measureable outcome of interest prior to, and at multiple time points after, application of the stressor; and good predictive value for short- and long-term clinical outcomes. For example, the oral glucose tolerance test (OGTT) is a widely used measure of resilience to a carbohydrate load that simulates the real-world metabolic stressor of a meal. This test involves measurement of plasma glucose prior to and at multiple time points after oral ingestion of a standard mass of glucose. Conditions surrounding the test have been standardized, such as fasting for a minimum number of hours prior to test administration. Assays for plasma glucose are well established. Normative values have been defined, predictive models for a variety of long-term outcomes have been developed. In addition, physiologic mechanisms underlying responses during the test have been increasingly elucidated, which have informed therapeutic development for conditions involving impaired glucose tolerance. As a result, the OGTT is a useful clinical test for establishing diagnosis, predicting risk, and guiding intervention.

The availability of clinical tests of resiliencies could improve clinical management of older patients (e.g., inform choice of treatments). Understanding resiliencies may also offer better predictive value for short- and long-term health outcomes than static measures of function or indicators of disease. Assessing resiliencies may help determine survival or function beyond specific disease indicators. This is particularly important for clinical management of individuals with multiple chronic conditions, where no single disease drives outcomes. Insight into changes in resiliencies across the human lifespan could also reveal aging mechanisms underlying decrements in function as well as factors contributing to the maintenance of healthy aging phenotypes.

This FOA will utilize the UH2/UH3 Phased Innovation Awards Cooperative Agreement mechanism to support the exploratory/developmental nature of the research on resiliencies that is critically needed at this juncture. Projects should be conducted by an interdisciplinary team of clinicians, epidemiologists, biostatisticians, physiologists, and basic scientists. Given the level of funding available for the project, applicants are strongly encouraged to select no more than four specific resiliencies to be studied, in order to provide adequate attention to each selected. Because research on many differing types of resiliencies entails common techniques and can be done within a single population, a single study can be more efficient in collecting such information. In addition, because it is likely that differing resiliencies share common mechanisms, a study design that allows them to be studied in combination may allow insights not obtainable otherwise.

Study Timeline

The study will be conducted using a two-phase approach in which the first phase will develop essential methodology and resources, followed by a second-phase full-scale study focused on a limited number of selected resiliencies. Additional milestones or refinement of proposed milestones may be negotiated prior to award. NIA program staff will interact scientifically with the investigative team throughout the course of the project to coordinate interactions and sharing of resources between the members of the research team and other appropriate sources (e.g., identification of longitudinal cohorts which may be used to test predictive value of newly developed measures, facilitate translational research opportunities, coordinate exchange of information with other NIH initiatives on resiliencies) to accomplish the goals of this initiative.

Phase 1 (UH2)

Awardees will conduct the following types of activities:

1) Define phenotypic features needed for adequate characterization of the degree of resiliency of specific clinical responses to specific stressors, or combinations of stressors. Such properties could include metrics of status before stress, the magnitude of the stressor, and key outcomes or functions affected by the stressor. Characterizing of quantitative responses could include the degree of change induced by stressor and time course of recovery in response to stressor. For categorical responses (e.g., occurrence or non-occurrence of an adverse event following a stressor) such properties could include the diagnostic criteria for the adverse event and degrees of its severity, and the duration of post-stress follow-up to be considered.

2) Develop and/or select instruments to obtain information on these phenotypic features, and test the feasibility of using them in clinical settings (including potential uses of routinely collected clinical data). Selection of such instruments should take into account metric properties such as reliability and sensitivity to inter-individual differences, including high- and low-end extremes. Collection of such information on persons who are in ongoing longitudinal studies, or through follow-up visits with participants in completed longitudinal studies, is particularly encouraged.

3) Identify candidate measures that could predict, or correlate with, the degree of the specific resilience and/or identify potential mechanisms influencing the degree of resiliency. Such measures could include long-term predictors (e.g., phenotypic data from clinical records or longitudinal studies or analytes in stored biospecimens) and short-term predictors obtained from specimens or clinical data collected before or shortly after occurrence of a stressor (e.g., elective surgery). Criteria in considering potential measures should include availability of specimens, and measurement properties (e.g., reliability) with regard to their potential value in predictive models or identification of mechanisms influencing resiliencies.

4) Design and conduct pilot studies of novel biologic tests or assays, including provocative tests to simulate the stressor (or components of it) in safe controlled conditions, for the purposes of improving prediction and identifying contributory biologic mechanisms influencing resilience. These tests should include attention to the possible role of proposed fundamental biologic aging processes (e.g., cell senescence, altered mitochondrial function, changes in proteostasis, inflammatory mechanisms).

Phase 2 (UH3)

In Phase 2, based on analyses from Phase 1, the awardee with conduct a study with a sufficient population and follow-up period to:

1) Generate models to improve short-term and long-term prediction of the selected resilience responses, and assess the predictive value of such models for clinical decision- making (e.g., screening surgical candidates, choosing cancer chemotherapy dose, considering preventive interventions to improve resiliency of responses when stressed). Studies on predictive value of resilience tests should include a focus on older adult populations who may have, or be at risk for, diseases of aging, geriatric syndromes, or other acute or chronic conditions common with advancing age. In addition, awardees may also focus on tests of resilience in younger adult populations to predict health outcomes in later life.

2) Assess potential biological mechanisms modulating processes that influence selected resiliencies, using specimens obtained from predictive tests or clinical care. These studies should include an evaluation of potential influence of biologic aging-related processes on specific resiliencies. In addition, the extent of shared mechanistic factors across more than one type of resiliency should be examined. The study should include an age distribution sufficient to allow an assessment of the extent to which age-related differences in mechanistic factors contribute to differences in resiliencies.

3) If sufficient preliminary evidence is available, awardees may also conduct preliminary studies to identify or validate therapeutic targets for interventions to enhance a specific type of resilience.

Transition from UH2 to UH3

Criteria to determine whether the award will transition from the UH2 phase to the UH3 phase include:

• Successful completion of awardee-specified milestones for the UH2 period of the project.
• Identification of putative phenotypic features which adequately discriminate between degrees of physiologic resiliency of individuals to specific stressors.
• Demonstrated analytical performance (including validation) of newly developed provocative tests of resiliencies and feasibility of their use in different clinical settings.
• Extent to which UH2 planning phase activities support the aims of the UH3 phase, including rationale for selected resiliency responses, plans for the development of short- and long-term prediction models for selected resiliency responses and elucidation of potential mechanistic factors underlying differences in physiologic resiliencies.
• Demonstrated effectiveness of strategies needed for successful conduct of the UH3 phase, such as recruitment, data management procedures, staff training, and IRB approvals.
• Potential of overall project to meet the goals of the initiative.

Research projects that are not appropriate for this FOA

Research projects focusing primarily on physiologic, psychological or behavioral responses to psychosocial stressors, their determinants and underlying mechanisms will be considered non-responsive to this FOA. However, a secondary focus on the effects of psychosocial factors as covariates influencing responses to physical stressors may be included.

Although limited studies in laboratory animal models to evaluate possible tests and correlations with analogous tests in humans may be included (and are encouraged where appropriate), a substantial focus on laboratory animal research testing is outside the scope of this FOA.

Relationships with other NIH resilience initiatives

This FOA addresses topics that complement those of NIH FOAs on resilience in laboratory animal models (RFA-AG-16-006) and on behavioral and psychosocial research on resilience (PAR-16-326).  Development of clinical measures of resilience may be informed by those in pre-clinical models, and vice versa. Also, an understanding of behavioral and psychosocial factors moderating responses to physical stressors may contribute to the development of clinical measures of resilience, as noted above. As such, exchange of ideas and information through meetings or other venues between the awardee supported through the present FOA and awardees of the abovementioned FOAs will be encouraged, and NIA program staff will facilitate these interactions as part of their role in this cooperative agreement

A webinar is planned to provide prospective applicants the opportunity to receive information and ask questions about the scientific scope of this announcement and technical details for applying. Please see www.nia.nih.gov/research/dgcg/resilience-rfa for information about timing and access.  

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

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:

o    Hispanic-serving Institutions

o    Historically Black Colleges and Universities (HBCUs)

o    Tribally Controlled Colleges and Universities (TCCUs)

o    Alaska Native and Native Hawaiian Serving Institutions

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

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

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

It is critical that applicants follow the instructions in the Research Instructions for 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:

Basil Eldadah, MD, PhD
Telephone: 301-496-6761
Fax: 301-402-1784
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 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.

All instructions in the SF424 (R&R) Application Guide must be followed. The composition of the investigative team should reflect the multidisciplinary expertise needed to achieve the proposed aims.

All instructions in the SF424 (R&R) Application Guide must be followed. Applicants should include costs for travel of key PDs/PIs and other relevant study staff to Bethesda, MD for the annual in-person meetings of the research team. These meetings should take place during both UH2 and UH3 phases of the award.

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: Describe and clearly demarcate the specific aims for both phases (UH2 and UH3) of the proposed project. Identify up to four specific resiliencies to be developed in the UH2 phase with further validation and characterization of short- and long-term outcomes in the UH3 phase.

Research Strategy: Provide a rationale with accompanying preliminary data to justify the significance of the selected physical stressors, proposed measures and proposed study designs. Describe the goals and research approach with milestones for both phases of the proposed project, and distinguish clearly between the two phases. Describe any innovative aspects of the approach.

Each application should include milestones specific to the proposed project that will be reached by the end of the UH2 phase. Metrics to assess achievement of milestones should be fully explained in the application.

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

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

Appendix: 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 PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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

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.

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

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

See more tips for avoiding common errors.

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

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

Does the project address clinically important aging-related physical stressors and their outcomes?

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?

Does the composition of the investigative team reflect the multidisciplinary expertise needed to achieve the proposed aims?

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?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the 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 children, justified in terms of the scientific goals and research strategy proposed?

Are the milestones specified by the applicant realistic and appropriate for the proposed project? Will the proposed project lead to a better understanding of short- and long-term outcomes of the stressors and their underlying mechanisms? Are the selected tests of resilience likely to be feasible in clinical and research settings?

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.

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.

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.

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

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.

Not Applicable

Not Applicable

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.

Not Applicable

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).

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

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.

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 score.
• Will receive a written critique.

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

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

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

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.

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.

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

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

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

Cooperative Agreement Terms and Conditions of Award

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 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 the primary responsibility for:

• Defining the overall research objectives and approaches of the UH2/UH3 project.
• Determining experimental approaches, designing protocols, setting project-specific milestones and overseeing conduct of analyses and experiments.
• Overseeing and coordinating the effort of the multidisciplinary team and participating Institutions and ensuring their optimal interactions and integration in the conduct of research activities.
• Ensuring compliance with NIH policies, including protection of human subjects.
• Publication or oral presentation of work done under this agreement will require appropriate acknowledgment of NIA support, including the assigned cooperative agreement award number.
• 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 interact scientifically with the research team and may provide appropriate assistance, including assisting in research planning, suggesting studies within the scope of the research team's objectives and research activities, presenting experimental findings to the research team from published sources or from other relevant sources, participating in the design of experiments agreed to by the research team, participating in the analysis of results, and advising in management and technical performance.
• Contribute to publications and presentations resulting from the UH2/UH3 project, if appropriate.
• The Project Scientist will be a member of the research governing body. In all cases, the role of NIA will be to assist and facilitate and not to direct activities.
• Additionally, an NIA Program Official will be responsible for the normal scientific and programmatic stewardship of the award, including monitoring implementation of the data and research resource sharing plans and will be named in the award notice.

Areas of Joint Responsibility include:

Research governing body:

• The research governing body for the UH2/UH3 project consists of the leadership of the UH2/UH3 project and NIA staff (one voting member).
• The research governing body will be chaired by one of the UH2/UH3 PDs/PIs.
• The research governing body members will meet regularly to review and monitor progress, plan and design research activities, and establish priorities. Meetings may occur as regularly scheduled teleconferences and include at least 1 in-person meeting each year in Bethesda, MD over the course of the UH2/UH3 project period. The PI(s)/PD(s) will be responsible for scheduling the teleconferences and in-person meetings, as well as for preparing concise minutes from teleconferences and in-person meetings. The meeting minutes will be distributed to the NIA Program Office and to research team members within one week of the meeting.

Data Safety Monitoring Board:

• An independent Data and Safety Monitoring Board (DSMB), will be established by the NIA, since the research activities may involve use of novel test measures in vulnerable populations. The DSMB will review research progress and the safety of the study participants based on a safety monitoring plan and report to the NIA Program Office. The DSMB’s approval will be required before initiation of the UH2 phase of the project and prior to transition to the UH3 phase.
• The PD(s)/PI(s) of the UH2/UH3 will assume responsibility for reporting of the DSMB recommendations to their respective Institutional Review Board(s).

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 award governing body 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.

In addition the PDs/PIs of the UH2/UH3 must address and meet the following criteria to transition from the UH2 to the UH3 phase of the project:

• Successful completion of awardee-specified milestones for the UH2 period of the project.
• Identification of putative phenotypic features which adequately discriminate between degrees of physiologic resiliency of individuals to specific stressors.
• Demonstrated analytical performance (including validation) of newly developed provocative tests of resiliencies and feasibility of their use in different clinical settings.
• Extent to which UH2 planning phase activities support the aims of the UH3 phase including rationale for selected resiliency responses, plans for the development of short- and long-term prediction models for selected resiliency responses and elucidation of potential mechanistic factors underlying differences in physiologic resiliencies.
• Demonstrated effectiveness of strategies needed for successful conduct of the UH3 phase, such as recruitment, data management procedures, staff training, and IRB approvals.
• Potential of overall project to meet the goals of the initiative.

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

A final 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.

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.

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 registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: https://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726

Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Basil Eldadah, MD, PhD
National Institute on Aging
Telephone: 301-496-6761
Email: [email protected]

Ramesh Vemuri, PhD
National Institute on Aging
Telephone: 301-402-7700
Email: [email protected]

Robin Laney
National Institute on Aging
Telephone: 301-496-1472
Email: [email protected]

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.