RELEASE DATE:  September 24, 2003
RFA Number:  RFA-AR-04-003
Department of Health and Human Services (DHHS)

National Institutes of Health (NIH)

National Institute of Arthritis and Musculoskeletal and Skin Diseases 


o Purpose of this RFA
o Research Objectives
o Mechanism(s) 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

The National Institute of Arthritis and Musculoskeletal and Skin 
Diseases invites grant applications for research to advance our 
understanding of the role of the innate immune system in the 
etiopathogenesis of autoimmune rheumatic diseases.  Autoreactive B and 
T cells have been the traditional focus of autoimmune research.  Rather 
than act separately and sequentially, it has become apparent that an 
interplay between the innate immune system and the adaptive immune 
system results in either the adaptive immune response or the autoimmune 
response.  Advances have been made in understanding the basic 
immunology of innate immunity and its interaction with adaptive 
immunity.  The purpose of this RFA is to stimulate and encourage 
innovative and multidisciplinary research to translate this knowledge 
of innate immunity into an understanding of its role in the 
etiopathogenesis of autoimmune rheumatic diseases. The applications in 
response to this RFA may be for individual research projects (R01) or 
for exploratory/developmental grants (R21).  

Although apparently separate, the innate and adaptive immune systems 
are in a delicate balance with constant interaction.  The innate immune 
system which is nonspecific with rapid response kinetics but lacks 
memory, includes: effector cells (natural killer cells, gamma delta T 
cells, plasmacytoid dendritic cells, macrophages, neutrophils), 
cellular receptors (Fc receptors, Complement receptors, Scavenger 
receptors, Toll Receptors), effector proteins (complement, mannose 
binding lectin C-reactive protein, coagulation factors), and cytokines 
(TNF, Interleukin (IL)-1, Interferon (IFN)-gamma, IFN alpha and beta, 
IL-15 etc.).  On the other hand, adaptive immunity is specific with 
slow response kinetics and has memory and is primarily T and B cells 
and dendritic cells.

Autoimmune rheumatic diseases become apparent when there is measurable 
end-organ damage, characterized by the presence of autoantibodies 
produced by self-reactive B cells and/or the attack on self-tissues by 
self-reactive T cells.  The generation and/or persistence of these 
autoreactive cells may be due to the dysfunction of regulatory pathways 
of the innate immune system.  For example, specific gene-targeted 
mutations in mice result in defects in proteins of the innate immune 
system and an apparent failure in clearance of apoptotic cells and/or 
nuclear debris.  These animals develop a lupus-like syndrome 
characterized by autoantibodies to double-stranded DNA or nuclear 
components.  Deficiency in mannose-binding lectin correlates with 
earlier development and increased severity of rheumatoid arthritis in 
humans.  These studies suggest that innate immunity plays a protective 
role in maintaining self-tolerance.  However, innate immunity may also 
play a role in autoimmune disease pathogenesis.  Onset and severity of 
collagen-induced arthritis (CiA) is inhibited in mice that are 
deficient in the complement component, C5, and CiA can also be 
inhibited by antibodies to C5. In addition, Toll-like Receptors (TLRs) 
on autoreactive B cells may be involved in the generation of rheumatoid 
factors.  Finally, evidence that TLRs expressed on antigen-presenting 
cells can elicit differential cytokine secretion skews the CD4 T cell 
response, and suggests that conditions and timing may direct whether 
the promoting or the protecting nature of the innate immune system is 

The purpose of this solicitation is to encourage research to increase 
our understanding of the role of innate immunity in the 
etiopathogenesis of autoimmune rheumatic diseases.  Understanding the 
role of the innate immune system in the earlier events of the 
etiopathogenesis of autoimmune diseases could lead to prevention of end 
organ damage and earlier intervention in autoimmune rheumatic diseases.  
Further analysis and identification of innate immunity involvement 
during the progression of the disease may lead to intervention and 
disease attenuation, thus decreasing morbidity and improving quality of 

Relevant autoimmune rheumatic diseases covered under this RFA include, 
but are not limited to, systemic lupus erythematosus, rheumatoid 
arthritis, juvenile rheumatoid arthritis, scleroderma and 
spondyloarthropathies in adults and children. 

Collaborations or research teams combining interdisciplinary approaches 
between autoimmune disease researchers and experts in other related 
scientific fields are highly encouraged.  

Epidemiological and clinical treatment projects are beyond the scope of 
this RFA.

Appropriate research areas may include, but are not limited to the 

o development and evaluation of new experimental systems, including the 
generation of transgenic and other genetically engineered animal models 
to study cellular, molecular and genetic aspects of innate immunity in 
rheumatic diseases

o studies to identify molecular and cellular pathways of innate 
immunity that enable initiation, maintenance and/or perpetuation of 
rheumatic disease manifestations 

o examination and characterization of the interactive pathways between 
innate and adaptive immunity that lead to rheumatic diseases 

o development of approaches that inhibit the interactive pathways 
between innate and adaptive immunity that lead to rheumatic diseases

o immediate and long term effects of pharmacological and other 
interventions that inhibit innate immunity in rheumatic diseases 

o research correlating clinical findings with markers of the innate 
immune response in rheumatic diseases  

This RFA will use the NIH R01 (investigator-initiated research project 
grant) and the R21 (exploratory/developmental research project) 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.  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 

This RFA uses just-in-time concepts.  It also the uses the modular 
budgeting format. (See
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular budget format.  This 
program does not require cost sharing as defined in the current NIH 
Grants Policy Statement at  

R01 Applications: The R01 application may request a project period of 
up to four years and a budget for direct costs of up to $250,000 per 

R21 Applications: The R21 application may request a project period of 
up to two years with a budget for direct costs not to exceed $100,000 
per year, not including indirect costs for collaborating institutions, 
if any.

The R21 projects solicited under this RFA are exploratory/developmental 
grants.  In the context of this RFA, exploratory/developmental grants 
are to be used to either a) gather preliminary data to develop a 
research basis for a subsequent application through other mechanisms, 
i.e. R01, P01, or b) to explore the feasibility of an innovative or 
conceptually creative research question or approach that may not be 
justifiable through existing research to compete as a standard research 
project grant (R01).  Because innovative projects may require a 
preliminary test of feasibility, the R21 mechanism could provide short-
term support for such preliminary work.  Exploratory/developmental 
studies may not be used for large-scale undertakings, or to support or 
supplement ongoing research.

NIAMS intends to commit approximately $1,500,000 in FY 2004 to fund 
four to eight new grants in response to this RFA. 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 NIAMS 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. 

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 with the skills, knowledge, and resources necessary to 
carry out the proposed research are 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.   

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:

Elizabeth Gretz, Ph.D.
Director, Immunology and Inflammation Extramural Program 
Rheumatic Diseases Branch, NIAMS, NIH, DHHS
One Democracy Plaza
6701 Democracy Boulevard, Suite 800, MSC 4872
Bethesda, MD  20892-4872
Telephone: (301) 594-5032
FAX: (301) 480-4543

o Direct your questions about peer review issues to:

Teresa Nesbitt, D.V.M., Ph.D.
Chief, Review Branch, NIAMS, NIH, DHHS
One Democracy Plaza
6701 Democracy Boulevard, Suite 800, MSC 4872
Bethesda, MD 20892-4872
Telephone:  (301) 594-4953
FAX:  (301) 480-4543

o Direct your questions about financial or grants management matters 

Michael Morse
Deputy Chief, Grants Management Branch, NIAMS, NIH, DHHS
One Democracy Plaza
6701 Democracy Boulevard, Suite 800, MSC 4872
Bethesda, MD 20892-4872
Telephone:  (301) 594-3535
FAX:  (301) 480-5450
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:

Teresa Nesbitt, D.V.M., Ph.D.
Chief, Review Branch, NIAMS, NIH, DHHS
One Democracy Plaza
6701 Democracy Boulevard, Suite 800, MSC 4872
Bethesda, MD 20892-4872
Telephone:  (301) 594-4953
FAX:  (301) 480-4543


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 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 in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email:

Research Plan

The research plan (a-d) is limited to 25 pages for R01 applications and 
10 pages for R21 applications.  Applications that exceed the page limit 
will be returned without review.  An appendix may be included in the 
application; however, the appendix is not to be used to circumvent the 
page limit of the research plan.

For the R21 application, preliminary data supporting feasibility of 
approach are not required; however, if included, the section may not 
exceed 1 page.  In addition, a paragraph should be included in the 
Significance section of the application that specifies either 1) how 
the project presents a new direction for the work performed in the PI's 
laboratory or 2) the innovative nature of the research question or 
approach, and how it may advance the understanding of the role of 
innate immunity in rheumatic diseases.

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 includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at

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:
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 materials must be sent to:

Teresa Nesbitt, D.V.M., Ph.D.
Chief, Review Branch, NIAMS, NIH, DHHS
One Democracy Plaza
6701 Democracy Boulevard, Suite 800, MSC 4872
Bethesda, MD 20892-4872
Telephone:  (301) 594-4953
FAX:  (301) 480-4543
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.

Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NIAMS.  Incomplete applications will not be 

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 NIAMS 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 NIAMS Advisory Council.

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 

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, all R21 
applications will also be reviewed with respect to the following:

In the context of this RFA, the R21 exploratory/developmental grants 
are to be used to either: a) gather preliminary data to develop a 
research basis for a subsequent application through other mechanisms, 
i.e., R01, P01 or b) explore the feasibility of an innovative or 
conceptually creative research question or approach that may not be 
justifiable through existing research to compete as a standard research 
project grant (e.g., R01).

Preliminary data supporting feasibility of approach are not required.

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).
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 in the 
sections on Federal Citations, below).

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.


Letter of Intent Receipt Date:  November 19, 2003 
Application Receipt Date:  December 19, 2003
Peer Review Date:  June 2004
Council Review:  September 2004
Earliest Anticipated Start Date: September 2004


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.

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.

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).  The establishment of 
data and safety monitoring boards (DSMBs) is required for multi-site 
clinical trials involving interventions that entail potential risk to 
the participants.   (NIH Policy for Data and Safety Monitoring, NIH 
Guide for Grants and Contracts, June 12, 1998:  

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 
(; a 
complete copy of the updated Guidelines is available at   
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 

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 or 
ethical reasons not to include them. This policy applies to all initial 
(Type 1) applications submitted for receipt dates after October 1, 

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

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

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of 
research on hESCs can be found at and 
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see   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. 

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

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.

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 
( 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

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

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at 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 and92. 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

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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