Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute on Aging (NIA)
Funding Opportunity Title	The Role of the Cytoskeleton in Cellular Aging (R21/R33)
Activity Code	R21/R33 Phased Innovation Award
Announcement Type	New
Related Notices	NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015) NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications (November 18, 2015) June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same. August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications.
Funding Opportunity Announcement (FOA) Number	PAR-13-301
Companion Funding Opportunity	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.866
Funding Opportunity Purpose	The purpose of this FOA is to stimulate the development of innovative research strategies aimed at increasing the understanding of the molecular and cellular changes in the cytoskeleton that occur during the aging process. Applications considering the effect of age on factors such as cytoskeleton structure and function, the impact of the cytoskeleton on intracellular organelle interactions, and signaling or regulatory molecules controlling cellular architecture are encouraged. There is also interest in studying the role of the cytoskeleton in nuclear-cytoplasmic communications, and in spatio-temporal relationships during the aging process and in age-related diseases.

Posted Date	August 1, 2013
Open Date (Earliest Submission Date)	September 16, 2013
Letter of Intent Due Date(s)	Not Applicable
Application Due Date(s)	Standard dates apply, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Standard AIDS dates apply, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date	Standard dates apply
Expiration Date	September 8, 2016
Due Dates for E.O. 12372	Not Applicable

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

Broadly defined, the cytoskeleton is a complex array of three major protein systems: microtubules, intermediate filaments and actin/microfilaments. Each of these three cytoskeletal systems assembles into separate networks within cells. Taken together these three networks are comprised of proteins which represent the major architectural building blocks of both the cytoplasm (classical cytoskeleton) and the nucleus (nucleoskeleton) of vertebrate cells. Associated with the cytoskeletal networks are a large variety of accessory proteins that serve to control their assembly, disassembly, dynamic properties, ability to cross link to each other both homotypically and heterotypically, and to various organelles. These three cytoskeletal systems play fundamental roles in determining cell and nuclear shape, in cell locomotion and cell division, signal transduction, cell/cell and cell substrate adhesion and provide cells with their mechanical properties.

Because of their essential roles in many cellular functions, it is critically important to understand the changes that take place in these cytoskeletal systems during the normal process of cellular aging. At the present time, remarkably little is known about the role of the cytoskeleton in the normal aging process, even though it is well established that there are numerous changes in cytoskeletal systems that have become the hallmarks of age-related disorders.

To begin to address these shortcomings, the Division of Aging Biology of the National Institute on Aging (NIA) held an exploratory workshop on the Role of the Cytoskeleton in Cellular Aging in May, 2009. The group of experts, including both aging and cytoskeleton researchers, discussed the current status of the science, covering areas such as composition of the nucleoskeleton, intermediate filaments, microtubules, and microfilaments. It was concluded that there is a need to bring together experts from various cytoskeletal subspecialists and established aging researchers in order to stimulate interactions and collaborations. It was also determined that there is a need for both new descriptive and quantitative studies to better understand how the cytoskeleton changes during aging, and ideally this should involve studies in multiple organisms. Such studies could, for example, include descriptions of how aging influences changes in cytoskeletal morphology; changes in quantities and localization of protein; as well as alterations in protein modification patterns. Another area of potential impact in the aging field is the mitochondrion-cytoskeleton interface. Each of the three cytoskeletal systems is known to interact with mitochondria, and there are provocative clues in the literature that these interactions are important for regulating mitochondrial function.

Although information on the role of the cytoskeleton systems in aging is miniscule compared to the studies that have been carried out in actively growing cells, there are clues that attracting researchers to work on the changes in the cytoskeletal systems as a function of cell aging would pay tremendous dividends. Clues as to the relevance of the cytoskeleton and nucleoskeleton in normal aging come from human diseases which show the age dependent onset of clinical problems. One of the hallmarks of Alzheimer's disease (AD), for example, is the presence of neurofibrillary tangles within neurons, and these tangles are composed of the microtubule associated protein, tau. While the role of these tangles in the etiology of the disease is still not clear, the fact that several forms of familial AD involve mutations in the tau protein strongly suggests that this cytoskeletal protein plays an important role in the onset of this aging disease. In contrast to tau, virtually no attention has been paid to the roles of microfilaments and intermediated filaments in the pathogenesis of AD.

Other clues as to the relevance of the cytoskeleton and nucleoskeleton in normal aging come from studies involving mutations in contractile proteins and the nuclear form of intermediate filaments, the nuclear lamins. The conditions of patients bearing these mutations worsen with age, often leading to clinical manifestations such as cardiac hypertrophy, heart failure or sudden death from arrhythmias. The recent demonstration that the premature aging disease of children, Hutchinson Gilford Progeria Syndrome, is caused by mutations in nuclear lamin A has led to studies that strongly suggest that this nucleoskeletal protein is involved in changes in epigenetic regulation, DNA repair and senescence that accompany normal cell aging.

Cell death as a result of aging is believed to occur through an apoptotic pathway. Several studies suggest that the actin cytoskeleton can regulate the release of reactive oxygen species (ROS) from mitochondria, thereby playing an important role in the initiation of cell death. Other studies show that stabilizing f-actin with the drug jasplakinolide stimulates a cell-death pathway, while de-stabilizing the f-actin network by overexpressing the regulatory protein gelsolin inhibits apoptosis. There is also growing evidence that intermediate filaments modulate the motility and function of mitochondria, in addition to anchoring them in certain regions of the cell. In addition, microtubules are known to be the major tracks upon which mitochondria move to their positions within cells. Therefore, it is quite likely that studies of cytoskeletal/mitochondrial interactions will shed important new light on the normal cellular aging process.

Considering the importance of the cytoskeleton in cell function and the severe lack of understanding of how the different components of the cytoskeleton system are affected by the aging process, NIA has identified the following areas of research interest. The scope of this FOA is not limited to these:

• Develop a basic understanding of microtubule morphology and dynamics in aging tissues. For example, it is important to understand whether the microtubule cytoskeleton is over- or under-stabilized during aging in adult stem cells, in progenitor cells, or in terminally differentiated cells.
• Determine if there are polymorphisms of genes involved in the microtubule system, and if these are correlated with aging and disease.
• Determine to what extent does a damaged microtubule cytoskeleton affect transcriptional regulation in differentiated tissues? Changes in both nuclear architecture and gene expression have been shown to accompany the aging process. Since the nuclear envelope is connected to the microtubule cytoskeleton via various linker proteins, a change in microtubule organization and stability during aging could influence nuclear architecture. Studies are encouraged to determine whether perturbing the microtubule cytoskeleton in tissue specific cell types could cause changes in nuclear organization and gene expression.
• Determine if changes in the microtubule cytoskeleton affect the accuracy and efficiency of cell division in adult stem cells. An important aspect of aging is the declining ability of an organism to replenish the worn or damaged tissues with new cells. It would be important to determine how the aging microtubule cytoskeleton might contribute to this decline.
• Determine the changes in the mechanical properties of cytoskeletal intermediate filaments (IF) in normally aging cells. Since there is an emerging notion that older cells are mechanically stiffer it is certainly important to study the roles of IF as potentially causative factors in altering both the mechanical properties of the aging cell and their responses to external forces such as shear stress and stretch.
• Define the changes in the nucleoskeletal intermediate filament systems in aging cells: the nuclear lamins. It will be of great interest to determine whether changes in the nuclear lamins as a function of aging are involved in processes related to normal senescence such as alterations in DNA repair mechanisms, changes in nuclear transport and other essential nuclear functions.
• Cause-effect relationships: If the cytoskeleton is defective, and cell function is defective, how can we test whether the changes in the cytoskeleton cause the defects in cell function? Pharmacological perturbation of signaling pathways that regulate the cytoskeleton might be informative for aging questions since this direction might have the potential for therapeutic interventions.
• Gene dosage effects: It may also be of interest to look at gene dosage effects for genes involved in regulating the cytoskeleton and its associated proteins along with the signaling pathways that regulate it. Model organisms may be a good way to move forward in this area.
• Aging and actin signaling pathways. Examining pathways both upstream and downstream of the actin cytoskeleton itself might be an especially productive area for aging research. These include several pathways already widely implicated in aging, such as the mTOR pathway, the AMPK pathway through the role of phosphoinositides as central regulators of actin, and ROS pathways that have been shown to regulate actin in yeast and in vertebrate cells.

This FOA will utilize the R21/R33 phased innovation award mechanism. Applications for R21 support alone will not be accepted under this FOA and will not be reviewed. Although preliminary data are not required, it is recommended that applications include preliminary data if available, supporting the proposed concept. Applications should propose milestone-driven exploratory/feasibility studies for the initial 2-year R21 phase and describe how the concept will be further developed in proof-of-concept studies during the R33 phase. Clearly defined, quantifiable milestones should be listed in the application, along with a yearly timeline or chart to delineate the projects and milestones that make up the R21 and R33 phases. The milestones are to be included in the Research Strategy section of the application and will be evaluated as part of the scientific and technical merit of the R21/R33 application.

Partnerships between investigators with expertise in cytoskeleton biology and in aging research are encouraged. Applications may use the Multiple Principal Investigator option. Additional information on this option may be found at http://grants.nih.gov/grants/multi_PI/.

Proof -of-concept studies for the R33 phase may include, for example:

• Integrative physiological studies at the molecular, cellular and tissue levels,
• Validation experiments with larger number of samples,
• A transition from in vitro models to ex vivo studies or studies in model organisms,
• Expansion of samples to include tissues,
• Application of computational/modeling strategies,
• Further development and application of in vitro and in vivo imaging approaches.

Prior to the end of the second year, awardees will submit the R33 transition package, which includes the R21 progress report, which describes progress towards the initial milestones, and a clear description of how research during the R33 phase will be impacted by attainment of the R21 milestones. These materials will be reviewed by the NIA Program staff and then, if selected, will be transitioned to an R33 award without the need to submit a new grant application. R33 funding decisions will be based on the original R21/R33 peer review recommendations, successful completion of milestones, program priorities, and availability of funds. If an R33 award is not approved, the grantee may invoke its right to a 12 month no cost extension to the R21 award.

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New Resubmission Revisions The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Award Budget	Support for the R21 phase cannot exceed two years and total direct costs are limited to $275,000 over the R21 two-year period, with a maximum of $200,000 in direct costs allowed in any single year. The R33 award phase must be less than $500,000 in direct cost per year and cannot exceed three years. Application budgets need to reflect the actual needs of the proposed project. While treated as direct costs, consortium F&A does not apply toward any direct cost cap.
Award Project Period	The total project period for an application submitted in response to this FOA cannot exceed five years. Awards will support milestone-driven exploratory feasibility "proof-of-principle" studies (two year R21 phase), with possible rapid transition to expanded developmental (three year R33) phase.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

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 and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. 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.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

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

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

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, 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 forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

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.

The R21/R33 Phased Innovation Award application must be submitted as a single application

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 R21/R33 Phased Innovation Award application must be submitted as a single application with one Research & Related Budget component. The R21 and R33 cannot be funded in the same fiscal year.

Budget Justification: For each budget year, indicate if the requested budget is for the R21 phase or the R33 phase.

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

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

Specific Aims: Within the Specific Aims section, include headers titled "R21 Phase Specific Aims" and "R33 Phase Specific Aims". Under each header, state the specific objectives of the research and development effort, including the technical questions you will try to answer to determine the feasibility of the proposed approach. Since the R21 phase of this FOA is the exploratory/feasibility component, hypothesis testing, per se, may not be the driving force in developing such an application, and therefore, may not be applicable in the R21 phase. The R21 phase could include descriptive, novel and untested approaches.

Research Strategy:

Innovation: Include headers titled R21 Phase Innovation and R33 Phase Innovation, and address the Innovation for the R21 and R33 phases in the appropriate sub-section.

Approach: Include headers titled R21 Phase Approach and R33 Phase Approach, and address the Approach for the R21 and R33 phases in the appropriate sub-section.

Milestones and Timeline (limit, one half page): Provide a timeline with specific milestones for accomplishing the proposed research, including specific milestones for progression from the R21 phase to the R33 phase. Indicate when it is anticipated that essential components of the project (e.g., optimization of protocols, generation of reagents, critical experiments to verify the hypothesis, validation of novel tools or techniques) will be completed. The proposed timeline should be clearly delineated and should appear as the last element of the Research Strategy section.

The milestones proposed in the application should be well described, quantifiable, and scientifically justified to allow program staff to assess progress in the R21 phase. The milestones will be considered in evaluating the approach proposed by the investigator. A discussion of the milestones relative to the progress of the R21 phase and the implications of successful completion of the milestones for the R33 phase should be included. Applications lacking this information, as determined by NIH staff, will be returned to the applicant without review. The clarity and completeness of the R21/R33 application with regard to specific goals and feasibility milestones are critical.

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

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include 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 by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

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.

For this particular announcement, note the following:

The R21/R33 grant supports exploratory/developmental 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/R33 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will focus their evaluation on 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 R21/33 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.

Significance

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

Investigator(s)

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

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

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.

Milestones and Timeline

Are the proposed milestones and timeline feasible and appropriate for judging the success of the R21 work? Are the proposed milestones appropriate for determining whether the R33 phase should be awarded? Do the milestones and timeline establish feasibility for all aspects of the proposed R33 work?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

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

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

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

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

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

Renewals

Not Applicable

Revisions

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.

Applications from Foreign Organizations

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

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), 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.

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 the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants 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

Not Applicable

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

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

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

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

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

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: [email protected]

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
TTY: 301-451-5936
Email: [email protected]

Jos Vel zquez, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-6428
Email: [email protected]

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Linda Whipp
National Institute on Aging
Telephone: 301-402-7731
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 Parts 74 and 92.