It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

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

This Funding Opportunity Announcement (FOA) invites applications that expand on foundational research demonstrating generally improved emotional function and emotion regulation with aging, to further clarify the trajectories of change in emotion processing and linked neurobiological factors in adults who are aging normally, as well as in individuals with mild cognitive impairment (MCI), Alzheimer's disease (AD), and Alzheimer's disease-related dementias (ADRD). The goal is three-fold: to advance understanding of (1) normative maturational shifts in emotional processes, (2) how dysfunction in the integrative neural-behavioral mechanisms of emotional function might manifest in MCI and the early stages of AD/ADRD, and/or (3) how such dysfunction might account for any of the neuropsychiatric symptoms observed in AD/ADRD. Such studies may identify novel targets for interventions or prevention efforts, or provide clues to intervention strategies that might be applied to normalize emotion dysregulation or strengthen emotional resilience at different life stages in normal aging or disease stages in MCI and AD/ADRD.

NIA has supported foundational research on emotional function in aging, which suggests that, for most adults, normal aging is associated with general trends toward improved emotion regulation (increasing positive and decreasing negative affect, greater emotional stability, higher life satisfaction, a "positivity" bias in information-processing). This new funding opportunity underscores NIA's continued commitment to research in age-related changes in emotional function, and provides an opportunity to address remaining gaps in the study of emotional function in normal aging, as well as to extend this work beyond normal aging, to MCI and AD/ADRD.

Evidence suggests that, compared with younger adults, older adults often show superior emotion regulation capacities, employ different strategies for executive control of emotional information, and recruit different neural networks in performing affective tasks. Such patterns have been variously hypothesized to stem from increased motivation to maintain emotional well-being, learning more skillful and efficient emotion processing strategies, or compensatory adaptations to age-related brain changes. However, not all adults demonstrate the positive emotion regulation profiles that characterize adaptive aging. To date, there has been little mechanistic research focused on sources of individual variability in development and maturation of emotional regulatory functions or other aspects of emotional functioning. Thus, the psychological, behavioral, physiological, and neurobiological processes that account for variation in this age-related emotional adaptation remain poorly understood.

In addition, there has been little scientific investigation of the extent to which adults with MCI or AD/ADRD manifest or fail to show normative maturational shifts, or at what point(s) during the adult lifespan they may tend to diverge in emotion regulation trajectories. NIA seeks to stimulate new research that further elucidates the behavioral, psychological, physiological, and neurobiological trajectories of normal age-related change in affective function, as well as research that examines divergence from that normal trajectory in MCI and AD/ADRD.

It is also paradoxical that, despite a normative course of cognitive decline with age, many aspects of emotional function improve with age. Though attributed to improved emotional regulatory strategies, such strategies are believed to rely on the same cognitive control capacities that decline with aging. Numerous questions remain regarding the role of cognitive control in adaptive emotional aging, alternative strategies that older adults might employ to regulate emotion, the cognitive processes that undergird those strategies, and the causes of individual variation in the ability to engage these strategies with advancing age.

The National Institute on Aging seeks to stimulate new research that further elucidates the behavioral, psychological, physiological, and neurobiological trajectories of normal age-related change in affective function, as well as research that examines divergence from that normal trajectory in MCI and AD/ADRD. There is also a need for research to elucidate the neural, behavioral, and psychological mechanisms involved in the emotional dysfunction that characterizes neuropsychiatric symptoms in AD/ADRD.

Ideally, the studies proposed will examine multiple domains of emotional function to address the dynamic interactions among differentially maturing brain systems and psychological processes that determine normative trajectories of emotional aging. Additional studies will support mechanistic research on how age-related changes in emotion processing occur, and interact with neurobiological and neurobehavioral factors associated with MCI and AD/ADRD and account for the emergence of emotional changes and/or affective dysregulation in these disorders.

NIA is also interested in descriptive epidemiology employing longitudinal cohort studies to estimate adult neurodevelopmental changes relevant to emotion regulation processes and other aspects of emotional function. Specifically, research is needed to clarify points in the adult life course at which trajectories diverge for subgroups with successful cognitive aging, normative cognitive decline, MCI, and AD/ADRD; identifying both when trajectories diverge, and in which psychological and neurobiological processes.

In addition, NIA is interested in studies that (1) test the extent to which cognitive or motivational changes account for age differences in emotion regulation; (2) test the hypothesis that biases in attention or memory serve the purpose of regulating emotion; and (3) identify the strategies that confer success in emotion regulation and the contexts that undermine success. There is also a need for validation studies connecting lab paradigms to real world contexts.

NIA particularly encourages more research that attends to social, financial, and health inequalities in trajectories of emotional development through adulthood. This will involve recruiting more diverse samples to address the links between social and financial inequality and late-life emotional function. Finally, a life course perspective on this issue would help link the substantial developmental research on affective processes in childhood with that on aging. Both approaches have the potential to strengthen life-span developmental theories about age-related emotional change.

In AD/ADRD research, there is an unmet need for studies of the affective problems in patients that present some of the greatest challenges to caregivers, nursing staff, and family members: the dysregulation of patients' negative emotions (neuropsychiatric symptoms) including irritability, anger, melancholia, anhedonia, paranoia, and fear. These emotional states are difficult to manage clinically, often result in over-medication, and potentially result in social isolation, because they are so difficult for caregivers to handle. There is emerging evidence that precursors of these neuropsychiatric symptoms may be evident prior to onset of cognitive impairment, and may signal the earliest stages of disease. To date, there has been little attention in the field of affective science to these early psychological and behavioral changes (mild behavioral impairment) or to the neuropsychiatric symptoms that characterize more advanced AD/ADRD.

Mechanistic research is encouraged that assesses emotional processes dimensionally, integrating across multiple levels of analysis and employing cutting-edge methodology from such fields as social cognitive and affective neuroscience, psychoneuroimmunology, psychosomatic medicine, neuroimaging, neurophysiology, gene expression and epigenetics, neuroendocrinology, and lifespan developmental psychology. Mechanisms that account for adaptive or maladaptive affective function may be characterized at any level of analysis from molecular to social. Use of psychometrically sound assessment approaches is encouraged as well as direct observation of emotion processes, such as in response to emotion-evoking stimuli, situations, or scenarios. Ideally, the studies proposed will examine multiple domains of emotion processing to address, in aging adults, the key developmental concept of dynamic interactions among behavioral and brain systems that support successful (and unsuccessful) emotion function.

The particular adult age ranges over which maturational changes may be examined are not prespecified and should be determined to fit the specific research questions posed. Applicants are expected to provide compelling rationales for their age range selection. Applications may propose to include data spanning the full life course, provided the research questions posed are relevant to adult maturational and aging processes.

Applications may also propose work using animal models of age-related changes in emotional function, particularly those that hold potential for elucidating the role of early environments and exposures in shaping trajectories of emotional function over the life course. Projects proposing research in animal models should clearly articulate the relevance to human aging.

Areas of interest include, but are not limited to:

• Studies of affective regulation and associated behavioral, psychological, physiological, and neurobiological factors across the adult age span, and clarifying points in the adult life course at which trajectories may diverge for different subgroups;
• Studies to clarify points in the adult life course at which trajectories diverge for subgroups with successful cognitive aging, normative cognitive decline, MCI, and AD/ADRD, identifying both when trajectories diverge, and in which psychological and neurobiological processes;
• Studies that clarify how dysfunction in behavioral, psychological, physiological, and neurobiological processes related to affective function might account for any of the neuropsychiatric symptoms observed in AD/ADRD;
• Studies that integrate observational and experimental approaches to examine how normative age-related affective function manifests in real-world contexts;
• Studies that clarify/resolve the paradox of age-related improvement in emotional regulation in the face of age-related cognitive decline;
• Secondary analysis of or new data collection in life-span studies with assessments of emotional and cognitive function from early life, including studies that examine the impact of early adversity on maturation of adult affect regulation;
• Studies of emotional function in samples representing population variation in social and financial circumstances, to permit examination of the link between socioeconomic inequality and later life emotional development;
• Studies evaluating differences in the brain circuits or cortical areas recruited during emotional challenge or task performance as a function of age and whether such differences predict resilience against onset of disrupted affective symptoms in MCI or AD/ADRD or deterioration in those functions in these disorders; and
• Studies employing efficient multi-cohort designs to estimate adult neurodevelopmental changes relevant to emotion regulation processes.

Mechanistic Stage 0 (use-inspired basic research) is appropriate for this FOA. The full NIH Stage Model is outlined and described here: NIH Stage Model. Examples of Stage 0 research include experiments designed to test hypotheses about mechanisms involved in emotional function. This FOA is not intended to support the following types of studies:

• Applications that characterize adults' emotional status solely in terms of diffuse mood states (e.g., only via depression, anxiety or other such scales), lacking assessment of specific emotion processing and/or contextual components essential for a mechanistic understanding of changes in emotion regulation;
• Applications that assess emotion processes and emotion regulatory strategies or processes at only a single level of observation and analysis (i.e., without combining multiple levels/methods such as genetic, cellular, brain circuit, physiological, behavioral, self-report);
• Applications lacking a focus on maturational shifts in emotion processing during adult phases of the life cycle as a core feature of the research design; and
• Stage, I, II, III, IV, or V Clinical Trials. See: NIH Stage Model

The NIH Exploratory/Developmental Grant supports exploratory and developmental research projects by providing support for the early and conceptual stages of these projects. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact on the field.

Applicants are encouraged to consider the use of measures for behavioral and neurological function from the NIH Toolbox (www.nihtoolbox.org), particularly the cognitive and emotion batteries or subsets of these. Developed under the aegis of the NIH Blueprint for Neuroscience Research, the NIH Toolbox offers a set of brief, comprehensive, well-validated and normed assessment tools that are now available for use on the iPad (https://nihrecord.nih.gov/newsletters/2016/02_12_2016/story4.htm). These may be considered for use as the primary data collection measures or in conjunction with measures commonly used by the investigator(s). Use of the NIH Toolbox measures helps to build data collection with common measures across diverse study designs and populations, furthering the important goals of efforts such as the Precision Medicine Initiative (https://www.whitehouse.gov/precision-medicine; http://www.nih.gov/precision-medicine-initiative-cohort-program) and Big Data to Knowledge (https://datascience.nih.gov/bd2k/about) by allowing comparison of results and pooling of data across studies.

Applicants are also encouraged to consider the use of measures of behavior change targets in the domains of self-regulation, stress reactivity and resilience, and interpersonal processes available from the NIH Science of Behavior Change Measures Repository. Funded projects in the SOBC Research Network (https://commonfund.nih.gov/behaviorchange/fundedresearch) have developed experimental manipulations, assays, and/or measures (hereafter referred to as "assays" for brevity) to support an experimental medicine approach to behavior change research. The SOBC Measures Repository is accessible from the SOBC Research Network Open Science Framework (OSF) page at https://osf.io/zp7b4.

Applicants are also encouraged to review the Notice on enhancing the reproducibility of NIH-supported research through rigor and transparency (NOT-OD-15-103), and to incorporate appropriate features into the proposed research plans.

Measures and Study Design Resources:

• NIH Science of Behavior Change Common Fund Program: https://commonfund.nih.gov/behaviorchange
• NIH Science of Behavior Change Measures Repository: accessible from the SOBC Research Network Open Science Framework (OSF) page at https://osf.io/zp7b4
• NIH Toolbox (http://www.nihtoolbox.org)
• NIH Stage Model for Behavioral Intervention Development: NIH Stage Model

Reports from NIA/NIH Sponsored Workshops (active links):

• Network on Reversibility: https://www.nia.nih.gov/sites/default/files/d7/reversibility_meeting_summary_1_20_16_final.pdf
• Behavioral and Social Factors Related to Alzheimer's Disease: https://www.ncbi.nlm.nih.gov/pubmed/28976725
• ADRD Summit (including recommendations for research on Health Disparities): https://www.ninds.nih.gov/sites/default/files/ADRD2016_summit_council_rpt_508Cpdf.pdf
• Understanding Pathways to Successful Aging: http://sites.nationalacademies.org/dbasse/bbcss/pathways_to_successful_aging/
• Linking Behavioral and Social Factors to Health: https://www.nia.nih.gov/sites/default/files/d7/pathways-meeting-summary-report_0.pdf
• Positive Psychobiology: https://www.nia.nih.gov/sites/default/files/d7/2013_march_12-13_positive_psychobiology_rev06-26-13_final.pdf
• Mixed Emotions: https://www.nia.nih.gov/sites/default/files/d7/mixed_emoti-con_an_interdisciplinary_conference.pdf
• Social Neuroscience of Aging: https://www.nia.nih.gov/research/dbsr/social-neuroscience-aging
• Neuroeconomics of Aging Workshop: https://www.nia.nih.gov/research/dbsr/neuroeconomics-aging-workshop

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 from 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)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

• 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 Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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.

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, with the following additional instructions:

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

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

When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

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

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

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, NIH. Applications that are incomplete or non-compliant will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

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.

For this particular announcement, note the following:

The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

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?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

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?

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.

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.

Not Applicable

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

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.

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

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 Center for Scientific Review, 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.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications . Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

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.

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 https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.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 https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/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 https://www.hhs.gov/ocr/about-us/contact-us/index.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.

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.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

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

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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

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

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: http://grants.nih.gov/support/ (preferred method of contact)

Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)

Telephone: 301-945-7573

Luke Stoeckel, Ph.D.
National Institute on Aging (NIA)
Telephone:301-496-3136
Email: luke.stoeckel@nih.gov

Luci Roberts, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: roberlu@mail.nih.gov

Dr. Maribeth Champoux
Center for Scientific Review (CSR)
Telephone: 301-594-3163
Email: champoum@csr.nih.gov

Jeff Ball
National Institute on Aging
Telephone: 301-402-7732
Email: ballj@nia.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 Part 75.