Part I Overview Information


Department of Health and Human Services

Participating Organizations
 National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
National Institute on Aging (NIA) (http://www.nia.nih.gov)

Title:Membrane Associated Signaling Defects in Immune Cells with Aging (R21)

Announcement Type
New

NOTICE: Applications submitted in response to this Funding Opportunity Announcement (FOA) for Federal assistance must be submitted electronically through Grants.gov (http://www.grants.gov) using the SF424 Research and Related (R&R) forms and the SF424 (R&R) Application Guide. 

APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.

This FOA must be read in conjunction with the application guidelines included with this announcement in Grants.gov/Apply for Grants (hereafter called Grants.gov/Apply).

A registration process is necessary before submission and applicants are highly encouraged to start the process at least four weeks prior to the grant submission date. See Section IV.

Request For Applications (RFA) Number: RFA-AG-07-006

Catalog of Federal Domestic Assistance Number(s)
93.866

Key Dates
Release/Posted Date: October 5, 2006
Opening Date: November 15, 2006 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): November 17 , 2006
NOTE: On time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization). 
Application Submission/Receipt Date(s):  December 14, 2006
Peer Review Date(s): February/March 2007
Council Review Date(s): May 2007
Earliest Anticipated Start Date(s):  July 2007
Additional Information To Be Available Date (Activation Date): Not Applicable
Expiration Date: December 15 , 2006

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

Table of Contents


Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants

    A. Eligible Institutions
    B. Eligible Individuals
2. Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
    A. Submission, Review, and Anticipated Start Dates
          1. Letter of Intent
    B. Submitting an Application Electronically to the NIH
    C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
    A. Additional Review Criteria
    B. Additional Review Considerations
    C. Sharing Research Data
    D. Sharing Research Resources
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
    A. Cooperative Agreement Terms and Conditions of Award
3. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)

2. Peer Review Contact(s)
3. Financial/Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement


Section I. Funding Opportunity Description


1. Research Objectives

Purpose

The purpose of this FOA is to solicit grant applications for basic research to investigate how the cellular aging process alters immune synapse formation and signal transduction efficiency in cells of the immune system.  Projects are encouraged that utilize recently developed imaging techniques and biophysical methods to study the molecular dynamics of immune synapse formation and its function in immune cells obtained from aged animal models or elderly individuals.    

Background

As individuals age, their ability to mount an effective immune response to pathogens declines thereby leading to an increased incidence of morbidity and mortality from infectious diseases.  Moreover, vaccine efficacy is greatly reduced with age, and immunization of older individuals induces both a less robust cell mediated immune response and a reduction in protective antibodies.  One reason that cell mediated immunity decreases with age is the dramatically decreased proportion of naïve T cells and the increased proportion of memory T cells that develops in response to reduced thymic output of naïve cells and the exposure to multiple pathogens over the lifespan of an individual.  In addition, T cells from aged mice and humans display multiple defects early in the signaling cascade initiated by T cell receptor stimulation which include reduced proliferation, aberrant cytokine production, and reduced Ca 2+ influx, resulting in incomplete differentiation to T helper type 1 or type 2 effector cells (for review, see Linton and Dorshkind, 2004) During the process of T cell activation, a highly ordered immune synapse is assembled at the contact zone between two cells of the immune system.  The conventional view is that the T cell receptor (TCR) and other signaling molecules translocate to these platforms that serve to facilitate the signal transduction process.  This process is dependent upon the clustering of specialized membrane microdomains and the cytoskeletal-driven relocation of key signaling molecules into these supra-molecular activation clusters (Razzaq, et al., 2004).   Using confocal microscopy, it has been demonstrated that CD4+ T cells from aged animals do not form immune synapses with antigen presenting cells as efficiently as cells from young mice and that both the coalescence of membrane microdomains and the reorganization of the cytoskeletal apparatus required to relocate signaling proteins to the site of the immune synapse is perturbed, resulting in hyporesponsiveness of these cells (for review, see Akha and Miller, 2005 and Fulop et al, 2006)  Although the molecular basis for defective immune synapse formation is not known, it has been suggested that the properties of the plasma membrane and lipid rafts appear to be altered in aged T cells, and that they might contain an altered composition of lipid moieties (Larbi, et al, 2004).  Lipid rafts are specialized regions of the plasma membrane that contain cholesterol, sphingolipid, phospholipids and other lipid moieties in specific proportions and allow membrane localization of particular cytosolic signaling proteins containing specific lipid anchors.  Alteration of the plasma membrane lipid composition has been demonstrated to have a profound influence on cell signaling by modulating the localization of membrane associated signaling proteins   (Geyeregger, et al., 2005)   In addition, age-related alterations of lipid composition within these microdomains may alter the fluidity and coalescence of the microdomains required for optimal signal transduction and thereby perturb the localization, diffusion and conformation of signaling proteins resident in these domains.     Moreover, changes in the plasma membrane signaling domains of aged lymphocytes may be a result of other age-related processes including macromolecular damage from reactive oxygen species, post-translational modifications of protein and lipid moieties such as glycosylation, and changes in synthesis and turnover of plasma membrane components such that the accumulation of damaged lipid and protein molecules within the plasma membrane microdomains might reach a level resulting in impaired signal transduction. 

Recently it has been shown that when aged animals are forced to produce new naïve T cells by a variety of experimental interventions, their newly-generated T cells do not exhibit the typical age-related defects and instead are capable of robust responses to antigen, producing normal levels of IL-2 and providing normal cognate helper functions (Haynes, et al., 2005).  This suggests that the activation defects are related to the length of time that has elapsed between the generation of the cell and its encounter with an antigen, further supporting the hypothesis that alterations in the components of the plasma membrane signaling domains may have accumulated.  Furthermore, it has been noted recently that there are defects and/or delays in the activation of cell signaling pathways for several other cell types within the immune system, including neutrophils and macrophages, among others.  Therefore, alterations of plasma membrane microdomains could potentially have a significant effect on the quality or the efficiency of various cell signaling pathways.  Further study of alterations in the organization and function of the immune synapse in immune cells from aged animal models and /or aged individuals is of importance in generating strategies to improve immune system function in the elderly. 

The application of recently developed biophysical tools to the study of membrane microdomains has helped to advance our understanding of the properties and dynamics of the immune synapse and its role in initiating signal transduction in immune cells (for review, see Kenworthy, 2005).   For example, the use of high resolution imaging techniques such as confocal and multiphoton microscopy for real time imaging of signal transduction events have been used in conjunction with fluorescent labeling techniques such as FRET, FRAP, and quantum dot labeling to investigate the organization, composition and lateral mobility of protein and lipid moieties within signaling-associated membrane microdomains. In addition, advances in imaging technology have been essential in increasing our understanding of T cell activation and have allowed the real-time visualization of cytoskeletal rearrangements and diffusion of lipid moieties within the plasma membrane.   It is hoped that this FOA will foster the application of these techniques to investigate the effects of the cellular aging process on the efficiency of signal transduction in aged immune cells.    

Objectives and Scope:

The funding opportunity is intended to encourage basic research that will lead to the understanding of how the cellular aging process leads to defects in immune synapse formation and signal transduction in immune cells of aged individuals. Applications are sought both for the application of current methodology to the study of defective signaling in aged immune cells and for the development of novel techniques to study the composition and function of immune synapses in aged lymphocytes. Recently, various biophysical tools and imaging techniques have been developed to investigate the fundamental microstructure and dynamics of plasma membrane signaling complexes (Kenworthy, 2005). Investigators with significant interest in determining the composition, structure and/or function of signaling complexes in aged immune cells are particularly encouraged to apply. Proposed research projects that include the development and application of techniques to examine immune synapse composition and dynamics must be applied to lymphocytes or other immune cells that are obtained from aged animal models or to samples obtained from elderly humans to be considered within the scope of this FOA.  The following examples illustrate areas of high interest, but other relevant innovative projects are also encouraged.    

How does the structure and composition of the immune synapse change with the cellular aging process and how do these changes affect signal transduction efficiency, downstream signaling pathways and functional capacity of the immune cell?

How does cellular aging affect the lipid composition of the plasma membrane and how do these changes correlate with alterations in the efficiency of T cell/APC immune synapse formation and lymphocyte activation?  The effect of lipid composition on the microstructure of membrane microdomains and on lateral mobility of membrane associated signaling proteins are of interest.

How does aging of the immune cell affect the dynamics of recruitment and retention of key signaling molecules to the site of the immune synapse? 

How does aging of the immune cell affect membrane fluidity and coalescence of different subregions within the plasma membrane and how do these changes correlate with alterations in signal transduction efficiency in various immune cells?

How does aging of immune cells affect the dynamics of cytoskeletal rearrangements during the early stages of T cell activation and how is the translocation of signaling molecules to the immune synapse affected?  Which processes and/or steps in signaling pathways are inhibited by the changes in cytoskeletal rearrangements observed with aging of the immune cells

How are cytoskeletal-associated regulatory proteins altered with cellular aging?  The use of proteomic approaches to identify proteins that aid in the process of synapse assembly and stabilization, including both structural and regulatory cytoskeletal related proteins that may affect signal transduction efficiency in aged T lymphocytes is of interest.

References

Akha, A.A.S. & Miller, R.A. (2005) Signal transduction in the aging immune system. Current Opinion in Immunology, 17. 486-491.

Fulop, T., Larbi, A., Douziech, N., Levesque, I., Varin, A., & Herbein, G. (2006).   Cytokine receptor signaling and aging. Mechanisms of Aging and Development, 127, 526-537.

Geyeregger, R., Zeyda, M., Zlabinger, G.J., Waldausl, W., & Stulnig, T.M. (2005) Polyunsaturated fatty acids interfere with formation of the immunological synapse. Journal of Leukocyte Biology, 77, 680-688.

Haynes, L., Eaton, S.M., Burns, E.M., Randall, T.D. & Swain, S.L. (2005) Newly generated CD 4 T cells in aged animals do not exhibit age-related defects in response to antigen. J. Experimental Medicine,  201(6), 845-851.

Kenworthy, AK. (2005) Where do we go from here? Meeting Report on the Biophysical Society Discussion on 'Probing Membrane Microdomains', October 28-31, 2004, Asilomar, CA, USA. Traffic, 6(6), 518-23.

Larbi, A., Douziech, N., Dupuis, G., Khalil, A., Pelletier, H., Guerard, K.P., & Fulop, T. (2004) Age-associated alterations in the recruitment of signal-tranduction proteins to lipid rafts in human T lymphocytes. Journal of Leukocyte Biology, 75, 373-381.

Linton, P.J. & Dorshkind, K. (2004). Age-related changes in lymphocyte development and function. Nature Immunology, 5(2), 133-139.

Razzaq. R.M., Ozegbe, P., Jury, E.C., Sembi, P., Blackwell, N.M. & Kabourdis, P.S. (2004) Regulation of T-cell receptor signaling by membrane microdomains.  Immunology, 113, 413-426.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information


Mechanism of Support

This Funding Opportunity Announcement (FOA) will use the NIH R21 award mechanism.  The applicant will be solely responsible for planning, directing, and executing the proposed project. 

The R21 mechanism is intended to encourage new exploratory and developmental research projects.  For example, such projects could assess the feasibility of a novel area of investigation or a new experimental system that has the potential to enhance health-related research.  Another example could include the unique and innovative use of an existing methodology to explore a new scientific area.   These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact on a field of biomedical, behavioral, or clinical research.

Applications for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism.   Applications submitted under this mechanism should be exploratory and novel.  For example, long-term projects, or projects designed to increase knowledge in a well-established area, would not be appropriate for R21 awards. These studies should break new ground or extend previous discoveries toward new directions or applications.  Projects of limited cost or scope that use widely accepted approaches and methods within well established fields are better suited for the R03 small grant mechanism through the regular review cycle.  Information on the R03 program can be found at http://grants.nih.gov/grants/funding/r03.htm .

This FOA uses “Just-in-Time” information concepts. It also uses the modular as well as non-modular budget formats (see the “Modular Applications and Awards” section of the NIH Grants Policy Statement. Specifically, if you are submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs), use the PHS398 Modular Budget component provided in the SF424 (R&R) Application Package and SF424 (R&R) Application Guide (see specifically Section 5.4, “Modular Budget Component,” of the Application Guide).

Applications from foreign (non-U.S.) institutions submitted via Grants.gov using the SF 424 (R&R): Follow the Research & Related Budget Component Instructions. Complete and submit the RESEARCH & RELATED BUDGET forms. Do not complete or submit the PHS 398 Modular Budget component. See NOT-OD-06-096

2. Funds Available

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIA provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

The total project period for an application submitted in response to this funding opportunity may not exceed 2 years. Although the size of award may vary with the scope of research proposed, it is expected that applications will stay within the budgetary guidelines for an exploratory/developmental project. Direct costs are limited to $275,000 over a two-year period, with no more than $200,000 in direct costs allowed in any single year. Applicants may request direct costs in $25,000 modules, up to the total direct costs limitation of $275,000 for the combined two-year award period.

The National Institute on Aging (NIA) intends to commit approximately $1,500,000 dollars in FY2007 to fund approximately 6-8 applications.

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.

Facilities and Administrative (F&A) costs requested by consortium participants are not included in the direct cost limitation. See NOT-OD-05-004, November 2, 2004.  

Section III. Eligibility Information


1. Eligible Applicants

1.A. Eligible Institutions

You may submit an application(s) if your organization has any of the following characteristics:

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research as the Project Director/Principal Investigator (PD/PI) 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.

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria

Applicants may submit more than one application, provided each application is scientifically distinct.

Section IV. Application and Submission Information


To download a SF424 (R&R) Application Package and SF424 (R&R) Application Guide for completing the SF424 (R&R) forms for this FOA, link to http://www.grants.gov/Apply/ and follow the directions provided on that Web site.

A one-time registration is required for institutions/organizations at both:

PDs/PIs should work with their institutions/organizations to make sure they are registered in the eRA Commons.

Several additional separate actions are required before an applicant institution/organization can submit an electronic application, as follows:

1) Organizational/Institutional Registration in Grants.gov/Get Started

2) Organizational/Institutional Registration in the eRA Commons

3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.

Note that if a PD/PI is also an NIH peer-reviewer with an Individual DUNS and CCR registration, that particular DUNS number and CCR registration are for the individual reviewer only. These are different than any DUNS number and CCR registration used by an applicant organization. Individual DUNS and CCR registration should be used only for the purposes of personal reimbursement and should not be used on any grant applications submitted to the Federal Government.

Several of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered in both Grants.gov and the Commons. The NIH will accept electronic applications only from organizations that have completed all necessary registrations.

1. Request Application Information

Applicants must download the SF424 (R&R) application forms and SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

Note: Only the forms package directly attached to a specific FOA can be used. You will not be able to use any other SF424 (R&R) forms (e.g., sample forms, forms from another FOA), although some of the "Attachment" files may be useable for more than one FOA.

For further assistance, contact GrantsInfo: Telephone 301-435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Prepare all applications using the SF424 (R&R) application forms and in accordance with the SF424 (R&R) Application Guide for this FOA through Grants.gov/APPLY

The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. There are fields within the SF424 (R&R) application components that, although not marked as mandatory, are required by NIH (e.g., the “Credential” log-in field of the “Research & Related Senior/Key Person Profile” component must contain the PD/PI’s assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see “Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.”

The SF424 (R&R) application is comprised of data arranged in separate components. Some components are required, others are optional. The forms package associated with this FOA in Grants.gov/APPLY will include all applicable components, required and optional. A completed application in response to this FOA will include the following components:

Required Components:
SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
PHS398 Modular Budget (all domestic applications)
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist
Research & Related Budget (foreign applications only)

Optional Components:
PHS398 Cover Letter File
Research & Related Subaward Budget Attachment(s) Form

PHS398 Modular Budget or Research & Related Budget, as appropriate (See Section IV.6., “Special Instructions,” regarding appropriate required budget component.)

Foreign Organizations (Non-domestic (non-U.S.) Entity)

NIH policies concerning grants to foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at: http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260.

Applications from foreign organizations must:

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.

3. Submission Dates and Times

See Section IV.3.A for details.

3.A. Submission, Review, and Anticipated Start Dates
Opening Date: November 15, 2006 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): November 17 , 2006
Application Submission/Receipt Date(s):  December 14 , 2006
Peer Review Date(s): February/March 2007 
Council Review Date(s): May 2007
Earliest Anticipated Start Date(s): July 2007
Additional Information To Be Available Date (Activation Date): Not Applicable
Expiration Date: December 15 , 2006

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

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.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

Dr. Rebecca A. Fuldner
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231
Bethesda, MD 20814
Telephone: (301) 496-6402
Fax: (301) 402-0010
Email: FuldnerR@nia.nih.gov

3.B. Submitting an Application Electronically to the NIH

To submit an application in response to this FOA, applicants should access this FOA via http://www.grants.gov/Apply and follow steps 1-4. Note:  Applications must only be submitted electronically.  PAPER APPLICATIONS WILL NOT BE ACCEPTED. 

In order to expedite the review, applicants are requested to notify the Institute on Aging Scientific Review Office by email (NekolaM@nia.nih.gov) when the application has been submitted.  Please include the FOA number and title, PD/PI name, and title of the application.

3.C. Application Processing

Applications may be submitted on or after the opening date and must be successfully received by Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization) on the application submission/receipt date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the receipt date(s) and time, the application may be delayed in the review process or not reviewed.

Once an application package has been successfully submitted through Grants.gov, any errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two business days to view the application image.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Incomplete applications will not be reviewed.

There will be an acknowledgement of receipt of applications from Grants.gov and the Commons. Information related to the assignment of an application to a Scientific Review Group is also in the Commons. 

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See the NIH Grants Policy Statement.

6. Other Submission Requirements

The NIH requires the PD/PI to fill in his/her Commons User ID in the “PROFILE – Project Director/Principal Investigator” section, “Credential” log-in field of the “Research & Related Senior/Key Person Profile” component. The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see “Registration FAQs – Important Tips -- Electronic Submission of Grant Applications.”

Organizational DUNS

The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see “Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.”

Warning: Please be sure that you observe the direct cost, project period, and page number limitations specified above for this FOA. Application processing may be delayed or the application may be rejected if it does not comply with these requirements.

Research Plan Component Sections

While each section of the Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.   

All application instructions outlined in the SF424 (R&R) Application Guide are to be followed, incorporating "Just-in-Time" information concepts, and with the following requirements for R21 applications:

Research Plan Component Sections

Items 2-5 of the Research Plan component of the R21 application may not exceed 15 pages, including tables, graphs, figures, diagrams, and charts.

Preliminary data are not required but may be included if available.

While each section of the Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.   

Appendix Materials

The following materials may be included in the Appendix:

Do not use the Appendix to circumvent the page limitations of the Research Plan component. An application that does not observe the relevant policies and procedures may be delayed in the review process.

Foreign Applications (Non-domestic (non-U.S.) Entity)

Plan for Sharing Research Data

Not applicable

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement  http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each Non-Competing Grant Progress Report (PHS 2590). See Section VI.3., “Reporting.”

Section V. Application Review Information


1. Criteria 

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the National Institute on Aging in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

Applications submitted in response to this funding opportunity will compete for available funds with all other recommended applications. The following will be considered in making funding decisions:

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application.

Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important scientific health problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?  

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the PD/PI and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?  

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. See item 6 of the Research Plan component of the SF424 (R&R).

Inclusion of Women and Minorities in Research:
The adequacy of plans to include subjects from both genders and all racial and ethnic groups (and subgroups), as appropriate for the scientific goals of the research will be assessed.  Plans for the recruitment and retention of subjects will also be evaluated. See item 7 of the Research Plan component of the SF424 (R&R).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under item 11 of the Research Plan component of the SF424 (R&R) will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Not applicable

2.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement  http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each Non-Competing Grant Progress Report (PHS 2590), See Section VI.3., “Reporting.”

Model Organism Sharing Plan:  Reviewers are asked to assess the sharing plan in an administrative note. The sharing plan itself should be discussed after the application is scored. Whether a sharing plan is reasonable can be determined by the reviewers on a case-by-case basis, taking into consideration the organism, the timeline, the applicant's decision to distribute the resource or deposit it in a repository, and other relevant considerations

3. Anticipated Announcement and Award Dates

Not applicable

Section VI. Award Administration Information


1. Award Notices

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

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.

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. See Section IV.5., “Funding Restrictions.”       

2. Administrative and National Policy Requirements

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.

3. Reporting

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

Section VII. Agency Contacts


We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:  

Rebecca Fuldner, Ph.D.
Biology of Aging Program
National Institute on Aging
B7201 Wisconsin Avenue, Suite 2C/231
Bethesda, MD 20814
Telephone: (301) 496-6402
Fax:(301) 401-0010
Email:  FuldnerR@nia.nih.gov

2. Peer Review Contacts:

Dr. Mary Nekola, Chief
Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C/212
Bethesda, MD 20814
Telephone: (301) 402-7702
Fax:  (301) 402-0066
Email: NekolaM@nia.nih.gov

3. Financial or Grants Management Contacts:

Linda Whipp, Chief
Grants and Management Office
National Institute on Aging
Building Number, Room Number
7201 Wisconsin Avenue, Suite 2N/212
Bethesda, MD 20892-9205
Telephone: (301) 402-7735  
Fax: (301) 402-3672  
Email: WhippL@nia.nih.gov

Section VIII. Other Information


Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45 CFR 46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (“NIH Policy for Data and Safety Monitoring,” NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement. Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research” (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the SF424 (R&R) application; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process, please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools, including the Authors' Manual.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (HHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the HHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles.  Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This FOA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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