Required Application Instructions

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

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The goal of this program is to test whether or not ages of laboratory animals can be an important consideration in experiments on disease pathology, response to therapy, intervention or environmental exposure. This applies to degenerative conditions as well as overt diseases.

This FOA will be used to support demonstration projects by researchers already studying diseases, conditions or environmental factors. The funds will be available solely to undertake additional studies using aged animal models in order to meet the scientific goals of this FOA. Applicants must have a published animal model and they must have an ongoing and independently funded program of research to study that model. That active funding may be from U.S. government and/or non-governmental sources. Therefore, studies supported by this FOA are separate from ongoing research and will be restricted to achieving the goals of this FOA. The funds will be awarded in two phases, using a -bi-phasic UH2/UH3 mechanism. Meeting the benchmarks will be required for continuation during the UH2 phase and for transition to the UH3 phase; an Administrative Review panel will determine whether benchmarks are being met. These are described below, in greater detail.

Success in these areas will lay the foundation for a systematic improvement in the use of aged animals for basic research into aging-related conditions, diseases and responses to interventions and environmental exposures.

Many animals have been used to study human conditions and diseases. The majority of studies of human conditions and diseases in laboratory animals are done using young animals. Young animals may be appropriate for study of human diseases that are prevalent in young humans. Conversely, older animals may be more appropriate for study of human diseases that are prevalent in older humans. For purposes of this Funding Opportunity Announcement, older animals are those with ages greater than the 75% survival level observed for that species and strain; e.g., 24 months for a C57BL/6 female mouse (life expectancy of approximately 32 months). When regarded as a model for humans, this can be viewed as approximating 55-60 year-old humans (assuming a life expectancy of 78 years). Using this criterion, it is possible to identify the requisite ages of older laboratory animals for many commonly used rodent species and strains. For further information, please refer to: https://www.nia.nih.gov/research/dab/aged-rodent-colonies-handbook/strain-survival-information.

The underlying assumption is that aged milieu of the organism has an impact on the disease, condition or response to intervention or environmental condition. The impact of age might be observed in the severity of the condition or disease, or in the response to intervention or environmental challenge. While this is a reasonable assumption and it is testable there have been obstacles to performing such studies: they are more costly and take more time than studies with young animals. Nevertheless, studies in older animals may be critical to advancing basic research and translational studies from animal models to human populations where aging is itself known to impact the condition, disease or response. To test this assumption, this FOA will provide funds for demonstration projects to address two questions: 1. Does the age of the animal influence experimental outcomes? 2. Are older animals better models of experimental studies for conditions, interventions, diseases or exposures for which aging is a risk factor of the human condition (for which the model was developed)?

Each UH2/UH3 application should be structured to meet the benchmarks, with the primary goal of the UH2 phase focused on breeding enough aged animals in preparation for meeting the primary goal of the UH3 phase which is to test the hypothesis that "Older ages of animals impact the experimental outcomes." The UH2 phase of the application should also be structured for initial testing of critical experimental parameters, which the applicant will identify as benchmarks (see below).

Major Benchmarks of the UH2 phase:

1. Breed cohorts for studies using older animals. Plans should account for loss of animals due to aging. Animals will be maintained to ages at least up to the 75% survival level (as described above).

2. Determine feasibility of using aged animals by preliminary testing of key experimental features and outcomes essential to proceed to the UH3 phase of the study. These benchmarks may be model-specific.

Major Goal of the UH3 phase:

The major goal is to test the central hypothesis: Older ages of animals impact the experimental outcomes. To achieve this, the applications will focus on outcomes that include:

1. Characterization of the degenerative condition or disease in the older animals versus young adults.

2. Characterization of the parameters of treatment, intervention or response to exposure in the older animals versus young adults

All applications will test the same hypothesis: Older ages of animals impacts the experimental outcome. Therefore these applications are inherently observational, whether or not the existing animal model has been designed or established to test a molecular mechanism as part of the experimental readout. The key feature of studies proposed in response to this FOA is testing whether age is a significant parameter in the experimental outcomes. Therefore, testing whether an already proposed mechanism is affected by age of the experimental animal may be included, but proposing new tests of a mechanism is not required in the application (see below on "Characteristics of Responsive Applications).

Progression to the UH3 stage will be determined by an Administrative Review Panel (see Benchmarks, below). In order to advance to UH3 status, laboratories must meet those benchmarks, some of which are considered general and are described in this FOA and some of which are model-specific and will be proposed by the applicant.

Detailed instructions for the UH2/UH3 application are found in Section IV.2., in the PHS 398 Research Plan section.

Benchmarks

All projects will be benchmark-dependent, and all UH2 awards will need to meet benchmarks to have an opportunity to move to the UH3 phase. Benchmarks are indicated above, and also in Section IV.2.

Transition to the UH3 award will depend on the successful achievement of general and model-specific benchmarks, the feasibility of study continuation, and the availability of funds. The UH3 awards will be made after administrative review of progress in the UH2 phase. There will be an Administrative Review Panel to monitor the benchmarks, composed of NIH extramural program staff from the participating NIH Institutes. This Administrative Review Panel may seek outside expert opinion. The Administrative Review Panel will meet annually, but may meet ad hoc if circumstances warrant. The decisions of this Administrative Review Panel may not be appealed.

Meetings and Workshops:

One teleconference or internet-assisted "kickoff meeting" will be held at the beginning of the award period as an organizing workshop together with NIH staff, including representatives from the institutes supporting the awards. This organizing workshop will go over current best practices for developing animal cohorts for aging studies and information needed by veterinarians for dealing with aging animal cohorts. The NIH will provide experts on the technical issues of developing aging cohorts and veterinary practices associated with aging animals; these experts may be intramural or extramural scientists.

A second meeting (workshop) will be held near the end of the UH2 phase or early in the UH3 phase of awards, for each laboratory to present progress on their animal cohorts and preliminary characterizations of the aging animal models.

A third and final meeting will be held during the last year of the UH3 phase for investigators to present findings on their aged versus young animal models.

Criteria to determine which UH2 projects will be continued into the UH3 phase will include these two general benchmarks and the study-specific benchmarks:

Animal Cohorts. Cohorts of sufficient sizes and ages must be developed during the UH2 phase of the award to permit experiments with older animals in the UH3 phase of the award. This requirement must be met, beginning with the first year of the award. Because awards are only made for existing animal models and the UH2 phase only supports breeding of these cohorts prior to the studies with older animals, and preliminary characterization (as described above), it will be necessary to have enough animals in breeding programs during the first year of the award, and in subsequent years, to perform the studies for the UH3 phase. If inadequate numbers are being bred that will be cause to end the award. There must be enough animals alive and aging to permit feasibility studies which are benchmarks of the UH2 phase and for the subsequent experiments of the UH3 phase; if inadequate numbers are alive then the award may be terminated.

Feasibility studies. These studies are expected during the final year of the UH2 phase and the first year of the UH3 phase. These include any gene-induction or dose-response experiments that are needed to establish that genes are expressed (including gene products proteins or RNA, as appropriate) in older animals, whether the model uses constitutive or inducible expression, and whether the animals survive long-term expression or the induction protocols (as appropriate to the model). For research programs using interventions, it might be necessary to titrate the dose or duration of interventions to establish toxicity or lethality in older animals. While this last category is in some respects the actual experiment expected for the UH3 phase if an intervention is the focus of the experiment it will still be necessary to do preliminary studies to determine that older animals can survive the intervention. These outcomes will be adjudicated by an Administrative Review Panel of NIH program officials to determine whether advancing to the UH3 phase is warranted.

Study-specific Benchmarks. Applicants must identify benchmarks for their specific models. For example, if an inducible transgene is used, investigators would test induction conditions for efficacy and lethality, using animals at older ages. Practically this means that to work with 18-24 month old animals during the UH2 phase, these animals must be bred at the beginning of the UH2 phase and enough animals must be alive for the determination of feasibility during the final year of a UH2 phase. In addition, enough of these animals be available (and aging) for experiments of the UH3 phase.

Research supported by this funding opportunity announcement is meant to support a range of studies which are of interest to different NIH Institutes. Research applications may address the following areas, but are not limited to the following areas of interest:

NIAID (Radiation and Nuclear Countermeasures Program)

• Assess the long-term effects on health and disease due to accidental ionizing radiation exposure caused by the intentional deployment of a nuclear device, industrial accident or accidental release;
• Assess how aging affects sensitivity to ionizing radiation and, conversely, how radiation affects aging;
• Characterize how gender affects sensitivity to and the long-term effects of ionizing radiation.

NIDCR

Chronic conditions influenced by aging include periodontal disease, xerostomia, chronic orofacial pain, and temporomandibular joint disorders (TMD). Potential topics might include:

• How chronic orofacial pain progresses in an aging system.
• How strategies for regenerating dental, oral and craniofacial tissue that show efficacy in younger animal models are altered in aging animals.
• Studies of disease-related, drug-induced and radiation-induced changes in salivary gland function in aging models.

NINDS

For relevant NINDS Programs information please see: http://www.ninds.nih.gov/funding/areas/index.htm

NIEHS

Projects that specifically focus on aging as a susceptibility factor for the health effects of environmental exposure(s). For the purposes of this FOA, environmental exposures of interest include heavy metals (Pb, Hg, Cd, etc), metalloids (As, etc), agro- and industrial chemicals and their manufacturing byproducts, air pollution and other inhaled toxicants, particulates or fibers, and fungal/bacterial or biologically derived toxins. Projects of thematic interest may include, but are not limited, to the following examples:

• The importance of the timing of exposure across lifespan for the effects on health and disease.
• Latent effects of early life exposure observed in aged animal populations.
• Identification of genetic loci that contribute to differential susceptibility to exposure observed in aged vs. younger populations.
• Effect of multiple environmental exposures, with at least one of the primary exposures identified as NIEHS-relevant discussed above, on alterations of disease trajectory throughout lifespan.
• Identification of biomarkers of cumulative exposure in aged populations.

NCI
NCI is interested in supporting pilot studies that utilize murine models of human cancers to assess whether the chronological age of the animal model is a critical factor in understanding the pathobiology of disease or response to intervention. Successful fulfillment of this FOA will lay the foundation for elucidating the mechanisms by which aging influences cancer development and response to therapy in basic and translational cancer research. Note that this RFA is limited to the expansion and aging of murine models in which the cancer can be induced at a later time point than is typically used for that specific model. NCI will not support the generation of new murine models or complex breeding programs. Murine models considered responsive must:

• represent models of strongly age-related human cancers;
• have been reported/described in peer-reviewed literature;
• be inducible. Examples of inducible models include, but are not limited to, genetically engineered mouse models (GEMMs) that conditionally regulate the expression of oncogenes and/or tumor suppressors or induction regimens that utilize chemical carcinogens or irradiation;
• parallel human cancer progression (i.e., the cancer modeled in a murine model should mimic the human counterpart;
• compare the effects of cellular transformation on cancer progression in old versus young mice and its correlation to human systems;

In addition:

• The ability to assess therapeutic outcomes in aged versus young adult murine models of human cancers would add significant value to the proposal. Only therapeutic approaches typically used (and reported in the literature) for each specific murine model is allowable. This FOA will not support the development of new therapeutic approaches.
• Applicants must define the aged time point at which the disease process (and therapeutic approach if appropriate) will be induced and studied. Aged time points for both male and female mice should be justified.

To be deemed responsive, applicants must have published in peer-reviewed publication(s) the animal model of the degenerative condition, disease, or intervention to be used for studies requested by this FOA.

To be deemed responsive, the laboratory must have live breeder pairs at the time of the application (see also award criteria).

To be deemed responsive, applicants must have a history of funding, current funding, and/or pending funding for this animal model on studies not addressing aging as an experimental parameter.. Prior to award, independent funding for studies on this animal model that do not address the issue of aging as an experimental parameter will be required in order for NIH to make an award, but this might not be known at the time of application or review. Therefore this will be evaluated by an Administrative Review Panel (see Section VI. 2. D.)

An application will be deemed nonresponsive if it proposes to create, develop or characterize an unpublished animal model for these studies. Such applications will not proceed to review.

An application will be deemed nonresponsive if it proposes to develop new assays for the animal model to be studied. Such applications will not proceed to review.

An application will be deemed nonresponsive it if proposes to use a premature or accelerated aging animal model. Premature or accelerated aging can be understood as animals with altered genotypes that yield earlier average-age of death compared to the parental strain (or species); altered genotypes would include transgenes or gene ablations. Such applications will not proceed to review.

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

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government - including the NIH Intramural Research Program
• 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 not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not 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).

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

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

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

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Ronald A. Kohanski, Ph.D.
Telephone: 301-496-6402
Fax: 301-402-0010
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.

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

The majority of funds in the UH2 phase should be for animal breeding and feasibility studies to meet the study-specific benchmarks. Salaries during the UH2 phase should be kept to a minimum. No more than 1.2 calendar months effort may be requested for the PD/PI or other key personnel. A majority of personnel costs would be in the UH3 phase.

The applicant must request funds for the UH2/UH3 PDs/PI(s) and key personnel to attend two in-person meetings mentioned above, that will be held in the Bethesda, MD area.

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:

The UH2 phase of the Research Plan should address:

• Breeding programs for the animals;
• Critical feasibility studies to determine whether the animals can be used at advanced ages;
• Study-specific benchmarks to be met prior to the UH3 phase.

The UH3 Phase of the Research Plan should address:

• Continued maintenance of aging animal cohorts; and
• Experiments appropriate to the animal model that will permit clear and well-supported conclusions about the impact of older ages on phenotypes associated with that animal model.

Specific Aims: Applications should state that the research plan will test the hypothesis that "Advanced age impacts the experimental outcomes of the animal model used to study a disease that, in humans, has aging as a major risk factor."

Research Strategy: The Research Strategy should be organized into sections on Significance, Innovation and Approach.

The hypothesis indicated in the Specific Aims section should be supported by details of the animal model, relating to disease, degenerative condition, environmental exposure, response to treatment, etc. These applications will constitute observational studies and need not be designed to test molecular mechanisms (please see the section on Characteristics of Responsive Applications).

The Significance section should include a description of the disease, condition, intervention or environmental exposure on two levels: first, the prevalence or importance of this for human health, touching upon what is known about adult age as a factor; and second, the animal model and its suitability for determining whether age of the animal might impact the outcomes of a study. This part of the application should highlight major findings with this model and the impact of these findings on the field. If the model has led to translational or clinical studies, this information should be included in the application. However, the existence of published translational or clinical studies is not required.

The Innovation section should address how work conducted under this project will identify the impact of organism age on biological research on disease models, models of degenerative conditions, response to environmental exposures or responses to interventions.

The Approach section should describe explicitly available information on the age(s) of the animal model as currently used in the laboratory and in publications with this model (their work and that of others with this model). Preliminary data using aged animals of the specific model are not needed for these applications. However, the applicants should provide information on any known age-related features of the parent species or strain; e.g. what are the diseases frequent in this species or strain and their development with age; causes of mortality, and what is known about toxicity or lethality in their parental species or strain. The application should identify the ages proposed to test the hypothesis, the number of animals that would be required for statistically rigorous data, the allowance for attrition from the aging animal cohort (due to death or culling). All studies should include consideration of the NIH Principles and Guidelines for Reporting Preclinical Research http://www.nih.gov/about/reporting-preclinical-research.htm.

The UH2 phase approach should include:

• Benchmarks for breeding cohorts of older animals. Plans should account for loss of animals due to aging. Animals will be maintained to ages at least up to the 75% survival level (as described above); and
• Benchmarks to determine feasibility of using aged animals. The benchmarks should identify preliminary tests of key experimental features and outcomes essential to proceed to the UH3 phase of the study.

The Approach section should include a subsection on "Breeding Animal Cohorts.

This subsection will include protocols for breeding cohorts for aging, calculations for numbers of animals that will be required with specific details for both UH2 and UH3 phases, and with clear evidence that animals needed for feasibility testing have been included, and attrition due to deaths expected while the cohort is aging have been taken into account. The application should provide the targeted minimum and maximum ages for the UH3 phase of the award; this is the phase where the central hypothesis will be tested (see above for the hypothesis). The application should propose to use both male and female animals in these studies, unless the disease or condition is specific to males or to females. The application should account for anticipated differences in male versus female lifespans in their laboratory animals, and consideration that there may be differences housing and culling males versus females (see the next paragraph). For information on lifespans of typical laboratory strains of rodents, please refer to this hyperlink for strain survival information on the NIA website. If using other animals for which lifespan information is not contained at the above hyperlink, please provide citations for relevant lifespan information. There should be included a detailed description of criteria to use when culling animals from an aging cohort.

Letters of Support: A letter of collaboration should be provided from the animal housing facility (veterinarian) stating awareness of the special issues related to aging animals and criteria that they expect to use when culling animals from an aging cohort. If necessary, collaboration with an animal facility or veterinarian experienced with aging animals can be provided.

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 Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

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

See Part I. Section III.1 for information regarding the requirements for obtaining a Dun and Bradstreet Universal Numbering System (DUNS) Number and for completing and maintaining an active System for Award Management (SAM) registration. Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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

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

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. 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.

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 components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

In order to expedite review, applicants are requested to notify the NIA Referral Office by email at [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

The budget requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits. NIH intramural scientists may not participate in this program as PD/PIs but may participate in the planning and development of the application. Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights. Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above. If selected, appropriate funding will be provided by the NIH Intramural Program

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? 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?

Specific to this FOA: has the applicant included an adequate description of the disease, condition, intervention or environmental exposure on two levels: first, the prevalence or importance of this for human health, touching upon what is known about adult age as a factor; second, suitability of the animal model for determining whether age of the animal might impact the outcomes of a study?

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 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? 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?

Specific to this FOA:

• For the UH2 phase, reviewers will evaluate: Adequacy and appropriateness of feasibility studies to determine whether the animals can be used at advanced ages.
• Adequacy and appropriateness of study-specific benchmarks to be met prior to the UH3 phase.

Have the benchmarks been delineated clearly and appropriately? Does the application provide adequate and relevant background information on ages used with this animal model, and on ages of humans in which the disease or condition manifests but where age is also considered a risk factor (age means adult age, and studies need to include animals at ages beyond the anticipated 75% survival for a properly housed cohort)?

Is the plan for the Breeding Animal Cohorts appropriate?

For the UH3 phase, reviewers will evaluate: Will experiments permit clear and well-supported conclusions about the impact of older ages on disease or condition (etc.) outcomes associated with that animal model?

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 five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether the information in the section "Veterinary Care for Aging Animal Cohorts" is appropriate.

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 Wide Association Studies (GWAS) /Genomic Data Sharing Plan.

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.

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

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

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

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.

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

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement (UH2/UH3), 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:

The PD(s)/PI(s) will have the primary responsibility for defining the details for the UH2/UH3 project within the guidelines of this FOA and for performing the scientific activities. The PD(s)/PI(s) will agree to accept close coordination, cooperation, and participation of NIH staff member who is the designated Scientific Officer on the award, as described under "NIH Scientific Officer Responsibilities." For institutions/organizations proposing multiple PDs/PIs, all PDs/PIs will share the rights and responsibilities of a grant awarded to an individual PD/PI, as described by the NIH Multiple Program Director/Principal Investigator Policy (http://www.grants.nih.gov/grants/multi_pi/).

The PD(s)/PI(s) of a UH2/UH3 project will:

• Determine experimental approaches, design protocols, set intermediate project benchmarks, and conduct experiments;
• Will report every six months the number of mice under breeding for the aging (experimental) cohorts. These reports will be by email to the NIH Scientific Officer and to the Program Officer for the award. These reports will be required during both the UH2 and UH3 phases of the award. The information will also be included in the annual progress reports;
• Will publish all results conducted under the UH2/UH3 award whether or not they demonstrate that age has an impact, and whether or not there are secondary negative or positive consequences of the engineered model organism (for example - but not limited to - a transgene appears beneficial in the young animal but causes early death or increases the occurrence of one or more diseases at later ages; control of gene expression in an inducible system becomes dysregulated (spontaneous) at older ages or is not restricted to the targeted organ or cell type);
• Participate in the kickoff teleconference and the two in-person meetings in the Bethesda, MD area.

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

NIH Scientific Officers will have substantial scientific and programmatic involvement that is above and beyond the normal stewardship role in awards through technical assistance, advice and coordination, as described below. However, the role of NIH Scientific Officer will be to facilitate, not direct, the activities, with a primary objective of ensuring that the goals of the FOA are met by the awardees. The Scientific Officer is not required to be from the administering Institute, Center or Office.

Additionally, a Program Official from the administering IC will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. A single individual may not serve the roles of both Program Official and Scientific Officer.

The NIH Scientific Officer will:

• Provide advice in the management and conduct of the-funded activities;
• Receive the six-month reports on animal breeding and relay those to the Administrative Review Panel.
• Retain the option to recommend withholding or reduction of support from any cooperative agreement that substantially: 1) fails to achieve its goals according to the benchmarks agreed to at the time of award; 2) deviates from the goals of the FOA; or 3) fails to comply with the Terms and Conditions of the award.
• May site-visit the laboratory and animal facilities of the PD(s)/PI(s).

Areas of Joint Responsibility include:

The PD(s)/PI(s) of each UH2/UH3 project will hold semi-annual discussions with the Scientific Officer of each UH2/UH3 project. More frequent ad hoc meetings may be held as requested by either the PD(s)/PI(s) or the Scientific Officer. These meeting will be held to:

• Discuss progress in meeting the goals and benchmarks of the UH2/UH3 projects;
• Discuss whether adjustments are needed in the protocols for animal breeding and veterinary care.
• Engage additional expertise, if necessary.

Administrative Review Panel:

The Administrative Review Panel (ARP) will be comprised of NIH Program Officers. The ARP will be responsible for determining independent funding for the animal model in the study, prior to the award. The ARP will be responsible reviewing and evaluating the progress. The Administrative Review Panel members will attend and participate in the required. The ARP will determine by vote whether benchmarks have been met and further funds will be awarded. The ARP will consider any requests for supplements to the awards (if any are requested), and will determine recommendations for these by vote..

The ARP will convene at least once each year; this may be in conjunction with a face-to-face meeting of the awardees, but will be held separately from that meeting.

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 arbitration. An Arbitration Panel will be convened, composed of three members: a designee of the Awardee, a member of the Administrative Review Panel who is not from the awarding NIH Institute but is chosen by the Administrative Review Panel; and a third designee with expertise in the relevant area who is chosen by the other two. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

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.

The PD/PI will report every six months the number of mice under breeding for the aging (experimental) cohorts. These reports will be made electronically, by email to the NIH Scientific Officer and to the Program Officer for the award. These reports will be required during both the UH2 and UH3 phases of the award. The information will also be included in the annual progress reports.

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

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

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
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 CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-710-0267

Ronald A. Kohanski, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-6402
Email: [email protected]

Francesca Macchiarini, M.S., Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3506
Email: [email protected]

Leslie A. Frieden, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-496-4263
Email: [email protected]

Roderick A. Corriveau, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5680
Email: [email protected]

Jonathan A. Hollander, Ph.D.
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-541-9467
Email: [email protected]

Susan McCarthy, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6200
Email: [email protected]

Biao Tian
Center for Scientific Review (CSR)
Telephone: 301-437-9858
Email: [email protected]

Linda Whipp
National Institute on Aging (NIA)
Telephone: 301-402-7731
Email: [email protected]

Tamia Powell
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2982
Email: [email protected]

Dede Rutberg, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: [email protected]

Tijuanna DeCoster, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: [email protected]

James R. Williams
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-541-1403
Email: [email protected]

Sean Hine
National Cancer Institute (NCI)
Telephone: 240-276-6291
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.