BASIC AND APPLIED STEM CELL RESEARCH FOR ARTHRITIS AND MUSCULOSKELETAL DISEASES

RELEASE DATE:  January 22, 2002

RFA:  RFA-AR-02-003

PARTICIPATING INSTITUTES AND CENTERS (ICs):

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
 (http://www.nih.gov/niams/)

LETTER OF INTENT RECEIPT DATE:  February 20, 2002

APPLICATION RECEIPT DATE:  March 20, 2002

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to become Principal Investigators
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

The National Institute of Arthritis and Musculoskeletal and Skin 
Diseases (NIAMS) invites applications for basic and applied stem cell 
research and for the development of innovative therapies for arthritis 
and musculoskeletal diseases.  The applications may be for individual 
research projects (R01) or for exploratory/developmental grants (R21). 
Pluripotent stem cells present in adult marrow, blood, and other 
tissues divide, and their progeny become committed to the multiple 
lineages of mesenchymal tissue, including cartilage, fat, tendon, 
muscle, fibroblasts, and marrow stroma.  Several studies suggest that 
these cells may be useful for examining mechanisms of progenitor cell 
differentiation and may be potentially useful for cell and gene 
therapy.  In addition, embryonic stem cells with the capacity for 
multilineage differentiation could constitute a renewable source of 
cells that could be employed to replace diseased or damaged tissue by 
cellular transplantation.  This Request for Applications (RFA) is based 
in part on the scientific opportunities identified in the conference 
"Stem Cell Biology: Potential and Promise."  A summary of the 
conference and research questions raised can be found at 
http://www.nih.gov/niams/reports/stemcellmeetsummary.htm.

RESEARCH OBJECTIVES

Stem cell research is an area of cutting edge scientific inquiry that 
provides new opportunities for researchers and clinicians working in a 
variety of fields, and it has the potential to lead to new treatments 
for arthritis and musculoskeletal diseases. A group of stem cell 
researchers and experts in other relevant fields was convened in June 
of 2000 to explore the new and emerging research findings in stem cell 
biology, identify research gaps and opportunities and foster research 
collaborations.  A summary of the conference and research questions 
raised can be found at:   
http://www.nih.gov/niams/reports/stemcellmeetsummary.htm.  The purpose 
of this announcement is to encourage pilot and developmental  projects 
(R21) and investigator initiated research projects (R01) that advance 
understanding of the biology of stem cells, the molecular mechanisms 
that govern formation of musculoskeletal tissues, and the  pathogenesis 
and treatment of arthritis and musculoskeletal diseases.  In addition, 
the initiative also seeks to promote the development and pilot testing 
of new therapeutic approaches involving stem cells.  Investigators 
wishing to propose research projects involving the use of human 
embryonic stem cells should be advised that this type of research may 
be subject to new regulations and/or restrictions because of the 
evolving complexity of regulatory issues.  The NIH has posted the 
Notice of Criteria for Federal Funding of Research on Existing Human 
Embryonic Stem Cells and Establishment of NIH Human Embryonic Stem Cell 
Registry (NOT-OD-02-005) at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  
Potential areas of research include, but are not limited to the 
following as related to arthritis and musculoskeletal tissue:  basic 
research on the biological functions of stem cells; developing and 
optimizing  methodologies for harvesting, expanding, and directing the 
differentiation of stem cell populations; elucidation of mechanisms of 
stem cell differentiation; and application of stem cell therapies to 
arthritis and musculoskeletal diseases.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) 
R01(investigator-initiated research project grant) and the R21 
(exploratory/developmental research grant) award mechanisms. Specific 
application instructions have been modified to reflect "MODULAR GRANT" 
and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 
Complete and detailed instructions and information on Modular Grant 
applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm.  
Responsibility for the planning, direction, and execution of the 
proposed project will be solely that of the applicant. Future 
unsolicited competing continuation applications will compete with all 
investigator-initiated applications and be reviewed according to the 
customary peer review procedures. The anticipated award date is 
September 30, 2002.

R21 Applications.  Use of this mechanism by investigators experienced 
in arthritis and musculoskeletal diseases research who wish to adapt 
stem cell methodologies to address basic and applied research questions 
is encouraged.  Also encouraged to apply are investigators with 
expertise in fields other than arthritis and musculoskeletal diseases 
who wish to establish new research programs on these diseases using 
stem cell technologies.

Exploratory/developmental studies are not intended for large scale 
undertakings nor to support or supplement ongoing research.  Instead, 
investigators are encouraged to explore the feasibility of an 
innovative research question or approach which may not be justifiable 
through existing research to compete as a standard research project 
grant (e.g., R01), and to develop a research basis for a subsequent 
application through other mechanisms, i.e., R01, P01.

Exploratory/developmental (R21) grants, may not exceed $75,000 per year 
in direct costs.  The total project period for an R21 application 
submitted in response to this RFA may not exceed three years.  These 
grants are non-renewable and continuation of projects developed under 
the R21 program will be through the traditional unsolicited (R01 or 
P01) grant programs.
Investigators proposing to conduct small, pilot/toxicity clinical 
trials are advised to review the NIAMS guidelines for preparation of 
clinical trial applications and the NIAMS guidelines for Data and 
Safety Monitoring Boards (http://www.nih.gov/niams.htm).

R01 Applications.  Because the nature and scope of the research 
proposed in response to this RFA may vary, it is anticipated that the 
size of an award will vary also.   Modular budgeting procedures apply 
for grants up to $250,000.  Specific R01 application instructions have 
been modified to reflect "Modular grant" and "Just-in-time" 
streamlining efforts.  Complete instructions and information on Modular 
Grants can be found at 
(http://grants.nih.gov/grants/funding/modular/modular.htm).

FUNDS AVAILABLE

The estimated funds available for the first year of support for the 
program are $1,000,000.  Because the nature and scope of the research 
proposed may vary, it is anticipated that the size of each award will 
also vary. Although the financial plans of the IC(s) 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. At this time, it is not known if this RFA will be reissued.

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
o faith-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.

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:
Dr. Bernadette Tyree
Cartilage and Connective Tissue Program
45 Center Drive, Room 5AS-25H
Bethesda, MD  20892-6500
Telephone:  (301) 594-5032
FAX:  (301) 594-4543
Email:  TyreeB@mail.nih.gov

Dr. Richard W. Lymn
Muscle Biology Program
45 Center Drive, Room 5AS-49E
Bethesda, MD  20892-6500
Telephone:  (301) 594-5128
FAX:  (301) 480-4543
Email:  LymnR@mail.nih.gov

Dr. William J. Sharrock
Bone Biology Program
45 Center Drive, Room 5AS-37A
Bethesda, MD  20892-6500
Telephone:  (301) 594-5055
FAX:  (301) 480-4543
Email:  SharrocW@mail.nih.gov

o Direct your questions about peer review issues to:

Dr. Tommy L. Broadwater
Review Branch 
45 Center Drive, Natcher Bldg. Rm. 5A25U
Bethesda, MD  20892-6500
Telephone:  (301) 594-4953
FAX:  (301) 480-4543 
Email:  broadwat@mail.nih.gov

o Direct your questions about financial or grants management matters to:

Melinda Nelson
Grants Management Branch
45 Center Drive, Natcher Bldg. Rm. 5A49F
Bethesda, MD  20892-6500
Telephone:  (301) 594-3535
FAX:  (301) 480-5450
Email:  nelsonm@mail.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:

Dr. Tommy L. Broadwater
Review Branch 
45 Center Drive, Natcher Bldg. Rm. 5A25U
Bethesda, MD  20892-6500
Telephone:  (301) 594-4953
FAX:  (301) 480-4543 
Email:  broadwat@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, 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/label-bk.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 
must be sent to:

Dr. Tommy L. Broadwater
Review Branch 
45 Center Drive, Natcher Bldg. Rm. 5A25U
Bethesda, MD  20892-6500

APPLICATION PROCESSING:  Applications must be received by 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.

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.  The CSR will not accept any application that is 
essentially the same as one already reviewed. This does not preclude 
the submission of substantial revisions of applications already 
reviewed, but such applications must include an Introduction addressing 
the previous critique.

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the (IC).  Incomplete applications will be 
returned to the applicant without further consideration.  If the 
application is not responsive to the RFA, CSR staff may contact the 
applicant to determine whether to return the application to the 
applicant or submit it for review in competition with unsolicited 
applications at the next appropriate NIH review cycle.

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 (IC) in accordance with the review 
criteria stated below.  As part of the initial merit review, all 
applications will:

o Receive a written critique
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 second level review by the National Arthritis and 
Musculoskeletal and Skin Diseases Advisory Council.

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 discuss the 
following aspects of your application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these 
criteria in assigning your application's overall score, weighting them 
as appropriate for each application.  Your 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, 
you may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

(1) SIGNIFICANCE:  Does your study address an important problem? If the 
aims of your application are achieved, how do they advance scientific 
knowledge?  What will be the effect of these studies on the concepts or 
methods that drive this field?

(2) APPROACH:  Are the conceptual framework, design, methods, and 
analyses adequately developed, well integrated, and appropriate to the 
aims of the project?  Do you acknowledge potential problem areas and 
consider alternative tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project 
challenge existing paradigms or develop new methodologies or 
technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to your 
experience level as the principal investigator and to that of other 
researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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, your 
application will also be reviewed with respect to the following:

o PROTECTIONS:  The adequacy of the proposed protection for humans, 
animals, or the environment, to the extent they may be adversely 
affected by the project proposed in the application.

o INCLUSION:  The adequacy of plans to include subjects from both 
genders, all racial and ethnic groups (and subgroups), and children as 
appropriate for the scientific goals of the research.  Plans for the 
recruitment and retention of subjects will also be evaluated. (See 
Inclusion Criteria included in the section on Federal Citations, below)

o 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:    February 20, 2002
Application Receipt Date:         March 20, 2002
Peer Review Date:                 TBA
Council Review:                   September, 2002
Earliest Anticipated Start Date:  September 30, 2002

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.

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD:  Research 
components involving Phase I and II clinical trials must include 
provisions for assessment of patient eligibility and status, rigorous 
data management, quality assurance, and auditing procedures.  In 
addition, it is NIH policy that all clinical trials require data and 
safety monitoring, with the method and degree of monitoring being 
commensurate with the risks (NIH Policy for Data Safety and Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

NCLUSION 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 AMENDMENT 
"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.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS:  The NIH maintains a policy that children (i.e., individuals 
under the age of 21) must be included in all human subjects research, 
conducted or supported by the NIH, unless there are scientific and 
ethical reasons not to include them. This policy applies to all initial 
(Type 1) applications submitted for receipt dates after October 1, 
1998.

All investigators proposing research involving human subjects should 
read the "NIH Policy and Guidelines" on the inclusion of children as 
participants in research involving human subjects that is available at 
http://grants.nih.gov/grants/funding/children/children.htm.

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://grants.nih.gov/grants/stem_cells.htm 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 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 PA 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.

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.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.846, and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review.  Awards are made under authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 
USC 241 and 284) and administered under NIH grants policies described 
at http://grants.nih.gov/grants/policy/policy.htm and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.

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.
http://grants.nih.gov/grants/guide/pa-files/PA-02-015.html.


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