ASSAYS OF STEM CELL FUNCTION IN CLINICAL AGING RESEARCH
RELEASE DATE: October 28, 2003
RFA Number: RFA-AG-04-009
Department of Health and Human Services (DHHS)
PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
(http://www.nih.gov)
COMPONENTS OF PARTICIPATING ORGANIZATION:
National Institute on Aging (NIA)
(http://www.nia.nih.gov)
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.866
LETTER OF INTENT RECEIPT DATE: December 19, 2003
APPLICATION RECEIPT DATE: January 21, 2004
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanisms of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations
PURPOSE OF THIS RFA
This Request for Applications (RFA) is to solicit proposals for: a)
clinical and epidemiologic studies to increase knowledge about the role
in humans of stem cell deficits, and of variation in stem cell numbers
and function, on health and functional outcomes in old age, and on age-
related physiologic changes and progression of chronic diseases, and/or
b) research to develop or improve assays of human stem cell number
and/or function that could be used in the types of studies indicated
above.
RESEARCH OBJECTIVES
As knowledge of stem cell biology increases, it enhances prospects to
develop and apply assays of stem cell number and function that could be
used in clinical and epidemiologic aging studies to examine the role in
humans of stem cell deficits, and of variation in stem cell numbers and
function, on health and functional outcomes in old age, and on age-
related physiologic changes and progression of chronic diseases. Such
assays may also be useful in evaluating response to stem cell
interventions, or other interventions that may alter stem cell number
or function. There has been progress in development of assays of stem
cell number and function in a variety of lineage for bone, blood,
muscle, fat, and cardiovascular tissues, but more research on the
validity and reliability of assays, and on development of new assays,
is needed for these and other tissues to realize the full potential for
clinical and epidemiologic aging research applications of measures of
stem cell number and function.
This RFA invites applications for research in two general areas:
1. For assays that are sufficiently reliable, valid, and feasible for
clinical interventions or epidemiologic aging research, applications
are invited for projects to:
o Evaluate the role of age-related stem and progenitor cell deficits as
risk factors for age related conditions. In addition, effects on age-
related physiologic changes such as alterations in body composition,
and on functional problems such as impaired responses to injury,
infections, chemotherapy, ischemic damage, or other stressors are of
interest.
o Determine long-term effects of variation in stem cell number or
function within the normal range during old age or earlier in life,
on health outcomes in old age. (E.g., retrospective studies using
stored blood or tissue samples.)
o Determine effects of factors that influence rates of change with age
in human stem cell populations, and their relationships to health
outcomes
o Evaluate interventions that might influence endogenous stem cell
production, survival, or function in older persons, and potential age-
related differences inefficacy or adverse effects of such
interventions.
o Determine effects of variation in stem cell number or function in old
age on responses to therapeutic or preventive interventions (e.g.,
hormonal, pharmacologic, or surgical interventions, and immunization.
2. For stem cell types of interest with regard to the above questions,
for which satisfactory assays for clinical and epidemiologic aging
research purposes have not yet been developed, proposals are invited
for research to determine and/or improve the validity, reliability, and
feasibility of assays of numbers and/or function of specific stem cell
types. The following topics are of particular interest:
o To improve validity of assays, more information is needed on the
relationship of specific markers to specific functional human cell
phenotypes. The potential gains in validity of approaches using
multiple markers to characterize stem cell populations also need to be
tested.
o More information is needed on the reliability of human stem cell
assays with regard to characteristics such as within-subject variation,
and differences in results from sampling from different tissue sites.
Research on strategies to improve reliability of assays is also
encouraged.
o Given limitations on the amount of tissue available from biopsy or
other human tissue samples, particularly from healthy volunteers,
research is needed on development and validation of approaches for
clinical and epidemiologic studies that can be performed with small
samples.
o Validation and determination of reliability of assays for various
circulating progenitor populations in blood. This is especially
important in regard to possibilities for larger-scale studies with more
frequent and/or long-term sampling to validate and apply assays of
specific circulating progenitor cell function. The potential for
sampling over longer periods is especially important for prospective
clinical and epidemiologic aging studies, since outcomes may be many
years removed from age-related changes in stem cell populations.
o Improvement, development, and validation of in vitro methods to assay
human stem cell number or function that reflect individual differences
among cell or tissue donors.
Proposals for assay validation or development in the above areas should
include, in the rationale for the proposed study, a description of the
particular clinical and/or epidemiologic aging research question(s)
that could be addressed better through the use of the assays to be
developed or validated.
Two topics of particular interest regarding both clinical and
epidemiologic studies using available assays, and the development of
new assays, are:
o Age-related changes in the distribution of early precursor stages in
lineages from more differentiated ones, and the potential clinical and
functional consequences of such changes.
o Potential systemic effects of age-related alterations in stem and
precursor cell properties in specific lineages, beyond their
consequences for their specific tissue (e.g., effects on other tissues
of cytokines or other circulating factors produced by the stem cells).
Potential applicants interested in conducting basic research on the
role of stem cells in tissue maintenance and disease in aging are
encouraged to review the companion NIA RFA AG-04-008 Biology of Stem
Cells in Aging. The full text of this RFA can be found on the NIA
website for Current Funding Opportunities at:
http://www.nia.nih.gov/data/fundbrowse.asp.
MECHANISMS OF SUPPORT
This RFA will use NIH R01 and R21 award mechanisms. As an applicant
you will be solely responsible for planning, directing, and executing
the proposed project. This RFA is a one-time solicitation. Future
unsolicited, competing-continuation applications based on this project
will compete with all investigator-initiated applications and will be
reviewed according to the customary peer review procedures. The
anticipated award date is September 30, 2004. Applications that are not
funded in the competition described in this RFA may be resubmitted as
NEW investigator-initiated applications using the standard receipt
dates for NEW applications described in the instructions to the PHS 398
application.
This RFA uses just-in-time concepts. It also uses the modular
budgeting format (see
http://grants.nih.gov/grants/funding/modular/modular.htm). This
program does not require cost sharing as defined in the current NIH
Grants Policy Statement at
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.
FUNDS AVAILABLE
NIA intends to commit approximately $1.5 million in FY 2004 to fund 5
to 6 new grants in response to this RFA. An applicant may request a
project period of up to 5 years and a budget for direct costs of up to
$250,000 per year under the R01 mechanism. 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 RFA are contingent upon the
availability of funds and the receipt of a sufficient number of
meritorious applications.
R21 applications for Exploratory/Developmental Research grants may
request up to two years of support with a combined budget for direct
costs of up to $275,000 for the two year period. For example, the
applicant may request $100,000 in the first year and $175,000 in the
second year. The request should be tailored to the needs of the
project. Normally, no more than $200,000 may be requested in any
single year. Exploratory/Developmental grant support is for new
project only; competing continuation applications will not be accepted
for this mechanism.
ELIGIBLE INSTITUTIONS
You may submit (an) application(s) if your institution has any of the
following characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges,
hospitals, and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign institutions/organizations
o Faith-based or community-based organizations
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to
carry out the proposed research is invited to work with their
institution 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 programs.
SPECIAL REQUIREMENTS
It is the intent of the NIA to provide support for stem cell research
through grant support and through promoting collaboration and
information sharing between investigators on projects of interest to
the NIA. Principal Investigators (PI) on grants resulting from this
RFA must participate in an annual workshop as convened by the NIA for
updates and exchange of information related to the projects supported
by these grants. In the event the PI is unable to attend, a mutually
acceptable designee may be agreed upon by the PI and NIA staff to
participate. Travel to this annual workshop, expected to be in
Bethesda, MD, should be included in the budget request in the
application.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA 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:
o Direct your questions about scientific/research issues to:
Chhanda Dutta, Ph.D.
Geriatrics and Clinical Gerontology Program
National Institute on Aging
7201 Wisconsin Avenue, Room 3C307 MSC 9205
Bethesda, MD 20892-9205
Telephone: 301-435-3048
E-mail: cd23z@nih.gov
o Direct your questions about peer review issues to:
Mary Nekola, Ph.D.
Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue, Room 2C212 MSC 9205
Bethesda, MD 20892-9205
Telephone: (301) 496-9666
Email: nekolam@nia.nih.gov
o Direct your questions about financial or grants management matters
to:
Cynthia Riddick
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue Suite 2N212 MSC 9205
Bethesda, MD 20892
Telephone: (301) 496-1472
Email: riddickc@nia.nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that
includes the following information:
o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA
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 at the beginning
of this document. The letter of intent should be sent to:
Mary Nekola, Ph.D.
Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue, Room 2C212 MSC 9205
Bethesda, MD 20892-9205
Telephone: (301) 496-9666
Email: nekolam@nia.nih.gov
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant
application instructions and forms (rev. 5/2001). Applications must
have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS)
number as the Universal Identifier when applying for Federal grants or
cooperative agreements. The DUNS number can be obtained by calling
(866) 705-5711 or through the web site at
http://www.dunandbradstreet.com/. The DUNS number should be entered on
line 11 of the face page of the PHS 398 form. The PHS 398 document is
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in
an interactive format. For further assistance contact GrantsInfo,
Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications
requesting up to $250,000 per year in direct costs must be submitted in
a modular grant format. The modular grant format simplifies the
preparation of the budget in these applications by limiting the level
of budgetary detail. Applicants request direct costs in $25,000
modules. Section C of the research grant application instructions for
the PHS 398 (rev. 5/2001) at
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants. Additional information
on modular grants is available at
http://grants.nih.gov/grants/funding/modular/modular.htm.
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev.
5/2001) application form must be affixed to the bottom of the face page
of the application. Type the RFA number on the label. Failure to use
this label could result in delayed processing of the application such
that it may not reach the review committee in time for review. In
addition, the RFA title and number must be typed on line 2 of the face
page of the application form and the YES box must be marked. The RFA
label is also available at:
http://grants.nih.gov/grants/funding/phs398/labels.pdf.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten
original of the application, including the Checklist, and three signed,
photocopies, in one package to:
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application and
all copies of the appendix material must be sent to:
Mary Nekola, Ph.D.
Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue, Room 2C212 MSC 9205
Bethesda, MD 20892-9205
Telephone: (301) 496-9666
Email: nekolam@nia.nih.gov
APPLICATION PROCESSING: Applications must be received on or before the
application receipt date listed in the heading of this RFA. If an
application is received after that date, it will be returned to the
applicant without review.
Although there is no immediate acknowledgement of the receipt of an
application, applicants are generally notified of the review and
funding assignment within 8 weeks.
The Center for Scientific Review (CSR) will not accept any application
in response to this RFA 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 an RFA, it is to be prepared as a NEW
application. That is, the application for the RFA 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.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR
and responsiveness by the (IC). Incomplete and/or nonresponsive
applications will not be reviewed.
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NIA in accordance with the review criteria
stated below. As part of the initial merit review, all applications
will:
o Undergo a process in which only those applications deemed to have the
highest scientific merit, generally the top half of the applications
under review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the National Advisory Council on
Aging
REVIEW CRITERIA
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.
In the written comments, reviewers will be asked to evaluate the
application in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals. The
scientific review group will address and consider each of the following
criteria in assigning the application’s overall score, weighting them
as appropriate for each application.
o Significance
o Approach
o Innovation
o Investigator
o Environment
The 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 problem? If the aims
of the application are achieved, how will scientific knowledge be
advanced? What will be the effect of these studies on the concepts or
methods that drive this field?
APPROACH: Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of
the project? Does the applicant acknowledge potential problem areas and
consider alternative tactics?
INNOVATION: Does the project employ novel concepts, approaches or
methods? Are the aims original and innovative? Does the project
challenge existing paradigms or develop new methodologies or
technologies?
INVESTIGATOR: Is the investigator appropriately trained and well suited
to carry out this work? Is the work proposed appropriate to the
experience level of the principal investigator and other researchers
(if any)?
ENVIRONMENT: Does the scientific environment in which the work will be
done contribute to the probability of success? Do the proposed
experiments take advantage of unique features of the scientific
environment or employ useful collaborative arrangements? Is there
evidence of institutional support?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the
following items will 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 criteria
included in the section on Federal Citations, below).
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. Plans for the recruitment and retention of subjects will
also be evaluated. (See Inclusion Criteria in the sections on Federal
Citations, below).
CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals
are to be used in the project, the five items described under Section f
of the PHS 398 research grant application instructions (rev. 5/2001)
will be assessed.
BUDGET: The reasonableness of the proposed budget and the requested
period of support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: December 19, 2003
Application Receipt Date: January 21, 2004
Peer Review Date: June 2004
Council Review: September 2004
Earliest Anticipated Start Date: September 30, 2004
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
REQUIRED FEDERAL CITATIONS
HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) 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
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 - Amended, October, 2001," published in the NIH Guide
for Grants and Contracts on October 9, 2001
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines are 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 new
PHS Form 398; 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 proposals for
research involving human subjects. You will find this policy
announcement in the NIH Guide for Grants and Contracts Announcement,
dated June 5, 2000, 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 (see
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.
PUBLIC 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 public 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 RFA 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.
STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:
The Department of Health and Human Services (DHHS) 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 DHHS Office for Civil Rights (OCR).
Those who must comply with the Privacy Rule (classified under the Rule
as covered entities ) must do so by April 14, 2003 (with the exception
of small health plans which have an extra year to comply).
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. Unless otherwise specified in an NIH solicitation, Internet
addresses (URLs) should not be used to provide information necessary to
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 RFA is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at
http://www.healthypeople.gov/.
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 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 NIH Grants Policy Statement can be
found at http://grants.nih.gov/grants/policy/policy.htm
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.
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