Release Date:  July 17, 2001

RFA:  RFA-AR-01-007

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Letter of Intent Receipt Date:  November 2, 2001
Application Receipt Date:       December 14, 2001



The National Institute of Arthritis and Musculoskeletal and Skin Diseases 
(NIAMS) invites applications for research on the pathogenesis of 
neuropsychiatric manifestations of systemic lupus erythematosus (NP-SLE) and 
on the development of innovative therapeutic approaches and diagnostics for 
this form of lupus.  The applications may be for individual research projects 
(R01) or for exploratory/developmental grants (R21). 
Systemic lupus erythematosus (SLE) is a multi-system rheumatic disease with a 
wide variety of associated clinical neurological and psychiatric syndromes 
including cognitive, behavioral, affective, and/or motor manifestations that 
may affect up to 75 percent of SLE patients.  Both morbidity and mortality 
remain high because of lack of understanding of the underlying mechanisms 
related to abnormal central nervous system (CNS) function.  In addition, 
progress has been hampered by the lack of specific diagnostic methods and 
therapeutic regimens.  This RFA is based in part on the scientific 
opportunities identified in the conference "CNS Manifestations of Systemic 
Lupus Erythematosus."  A summary of the conference and research questions 
raised can be found at


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 "Healthy 
People 2010" at  The two overarching 
goals of Healthy People 2010 are to (1) increase quality and years of healthy 
life and (2) eliminate health disparities.


Applications may be submitted by domestic and foreign for-profit and 
nonprofit organizations, public or private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal Government.  Applicants also may collaborate, through 
consultation or contractual agreements, with investigators at foreign 
institutions.  Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as Principal Investigators.


The mechanisms of support will include the investigator-initiated research 
project grant (R01) and the exploratory/developmental research grant (R21).

R21 Applications.  The purpose of the R21 projects solicited under this RFA 
is to gather preliminary data leading to the development of an investigator-
initiated research project (R01). Use of this mechanism is recommended by 
investigators experienced in lupus research who wish to adapt or apply 
neuroscience, vascular biology or other relevant methodologies to study NP-
SLE pathogenesis.  It is also recommended for investigators with relevant 
expertise (e.g., neuroscience, behavioral, vascular biology or others) 
interested in developing a program in NP-SLE.  In addition, the R21 mechanism 
can be used for projects where the aim is to gather pre-clinical data for new 

Exploratory/developmental studies are not intended for large-scale 
undertakings or to support or supplement ongoing research.  Instead, 
investigators are encouraged to explore the feasibility of an innovative 
research question or approach that may not be at a stage advanced enough to 
compete as a standard research project grant (e.g., R01).  The R21 mechanism 
can also be used 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, not including facilities and administrative (F&A) costs for 
collaborating institutions, if any.  The total project period for an R21 
application submitted in response to this RFA may not exceed 3 years.  These 
grants are nonrenewable and continuation of projects developed under the R21 
program will be through the traditional unsolicited (R01 or P01) grant 

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 

R01 Applications.  The individual research grant (R01) is a specific, 
circumscribed project to be performed by the named investigator(s) who has a 
specific interest and competency in an area of interest to this RFA. The 
total project period for an R01 application submitted in response to this RFA 
may not exceed 5 years.  Future unsolicited competing continuation 
applications will compete with all investigator-initiated applications and be 
reviewed according to the customary peer review procedures.

Because the nature and scope of the research proposed in response to this RFA 
may vary, it is anticipated that the size of an R01 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 Direct costs will 
be awarded in modules of $25,000, less any overlap or other necessary 
administrative adjustments.  F&A costs will be awarded based on the 
negotiated rates.

Investigators who wish to establish new collaborative research programs in 
NP-SLE with laboratories at the NIAMS Intramural Research Program, and apply 
for funding under this RFA, are encouraged to contact Dr. Barbara Mittleman, 
Director, Office of Scientific Interchange, NIAMS (


It is anticipated that for FY 2002, approximately $1.2 million total costs 
will be available for the first year of support for this initiative.  The 
specific number to be funded will depend on the merit and scope of the 
applications received and on the availability of funds.  Applicants may 
request up to 5 years of support for the R01. Exploratory/developmental (R21) 
grants may not exceed $75,000 per year in direct costs, not including F&A 
costs for collaborating institutions, if any.  The total project period for 
an R21 application submitted in response to this RFA may not exceed 3 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.


NP-SLE is an ill-understood clinical manifestation of systemic lupus 
erythematosus and constitutes one of the major causes of death among lupus 
patients.  Clincal expression of NP-SLE is diverse, may be intermittent or 
progressive, and can range from mild to severe. NP-SLE manifestations include 
diffuse encephalopathy, depression, cognitive dysfunction, memory loss, 
concentration deficits, dementia, anxiety syndromes, cranial neuropathies, 
cerebrovascular accidents, transverse myelitis, seizures, headaches, aseptic 
meningitis, pseudotumor cerebri, and lupoid sclerosis.  In general, a 
fluctuating course of disease rather than a rapid decline to dementia is 
characteristic.  Cognitive impairment can occur in isolation or in the 
context of other neurologic or psychiatric syndromes such as depression or 
psychosis.  The American College of Rheumatology (ACR) has developed a 
standard nomenclature for NP-SLE [Arth. Rheum., 1999, 42(4):599-608] using a 
1-hour battery of neuropsychological tests of cognitive function.

Certain deficits are specifically associated with particular serum 
autoantibodies.  In recent reports, lupus psychosis was found to be 
associated with the presence of antibodies directed against the carboxyl 
terminus of the ribosomal P proteins. A shared amino acid sequence between 
HLA-DQB1 and P peptides was strongly associated with anti-P antibodies in 
SLE, suggesting the presence of autoreactive T cells directed against P 
proteins. The mechanisms explaining these associations and their contribution 
to disease pathogenesis are uncertain. Antibodies may bind to cell-surface 
receptors on neuronal cells, and autoreactive T cells may produce cytokines 
that may contribute to organ inflammation. Vascular events also appear to 
contribute to CNS involvement in lupus. Intravascular thrombosis and 
vasculitis have been found associated with NP-SLE.  Other not-yet-defined 
mechanisms may also be involved. 

With the recent development of diagnostic and classification criteria for NP-
SLE, clinical research can now proceed to establish other associations with 
immune and nonimmune mechanisms of disease. Research in this area could 
improve significantly with the development of new techniques to assess organ 
involvement and with the development of new animal models to explore the 
pathogenesis of the disease.

The purpose of this announcement is to encourage exploratory/developmental 
projects (R21) and investigator initiated research projects (R01) that 
explore new approaches and hypotheses on the pathogenesis of NP-SLE. Further, 
projects exploring the natural history of the disease, new diagnostic 
modalities, and therapeutics are also encouraged. Areas of interest include 
but are not limited to: 

o Studies designed to discover the underlying mechanisms of nervous 
system involvement in SLE, including studies in new and existing animal 
models of disease.
o Advanced research projects to further describe clinical features of NP-
SLE and establish correlations with systemic and other organ 
manifestations, for example, correlation between CNS and peripheral 
o Hypothesis-generating studies of murine and human NP-SLE to examine the 
role of inflammatory mediators and inflammation of the central nervous 
system and/or its vasculature in NP-SLE pathophysiology, e.g., 
endothelial activation, immune complex deposition and effacement of the 
blood-brain barrier, extracellular matrix components, pericyte and 
microglial activation, abnormalities in neurotransmission and 
neurophysiology, autoantibodies such as antiphospholipid antibodies, 
abnormalities of coagulation, etc. 
o Studies aimed at dissecting the relative role of the immune and 
vascular processes in pathogenesis of NP-SLE.  
o Epidemiology studies of NP-SLE, including studies of natural history of 
disease and disease outcomes, and influence of ethnicity and race in 
disease incidence and outcomes.  
o Studies to characterize the cognitive, behavioral, affective, and motor 
manifestations of NP-SLE and their relations to disease outcome and 
quality of life.  
o Assessment of structural and functional aspects of the nervous system 
in SLE (i.e., by neuroimaging or neuropathology).
o Evaluation of prospective biomarkers of CNS involvement in lupus, 
including biological, imaging, and other modalities that reflect normal 
or abnormal biological processes potentially relevant to NP-SLE, with 
emphasis on those that distinguish transient or reversible vs. 
irreversible processes.
o Treatment studies and linked pathophysiology research projects for 
prevention of damage and progressive deficits.
o Neurobehavioral evaluation of murine models of SLE.
o Evaluation of neurobehavioral effects secondary to SLE treatment.
o Development and pilot testing of new therapeutic approaches, including 
alternative and complementary medicine.    
 NOTE: Research project proposals in NP-SLE may include resource development, 
e.g.,  organizing core reference laboratories and/or reagents for specific 
tests, shared data collection protocols, possible central data analysis, and 
databases.  However, the development of the core should not be the sole focus 
of the application. 
 It is the policy of the NIH that women and members of minority groups and 
their subpopulations must be included in all NIH supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided 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 research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
a complete copy of the updated guidelines is available at The 
revisions relate to NIH defined Phase III clinical trials and require (a) all 
applications or proposals and/or protocols to 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) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.
 Investigators also may obtain copies of the policy from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.
 It is the policy of the NIH 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, 
and is available at the following URL address:
 Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES. Program staff may also provide additional relevant 
information concerning the policy.
 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. Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

NIH policy requires education on the protection of human subject participants 
for all investigators submitting NIH proposals for research involving human 
subjects.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website:
 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.
 Prospective applicants are asked to submit, by November 2, 2001, a letter of 
intent that includes a descriptive title of the proposed research; the name, 
address, and telephone number of the principal investigator; the identities 
of other key personnel and participating institutions; and the number and 
title of this RFA. Although a letter of intent is not required, the 
information that it contains allows Institute staff to estimate the potential 
review workload. The letter of intent is not binding, does not commit the 
sender to submit an application, and does not enter into the review of a 
subsequent application. The letter of intent is to be sent (e-mail, fax, or 
post) to Dr. Tommy Broadwater at the address listed under INQUIRIES.

The PHS 398 research grant application instructions and forms (rev. 5/2001) 
at is to be used in 
applying for these grants. This version of PHS 398 is available in an 
interactive, searchable PDF format. Although applicants are strongly encouraged 
to begin using the 5/2001 revision of the PHS 398 as soon as possible, the NIH 
will continue to accept applications prepared using the 4/1998 revision until 
January 9, 2002.  Beginning January 10, 2002, however, the NIH will return 
applications that are not submitted on the 5/2001 version.  For further 
assistance contact GrantsInfo, Telephone 301/710-0267, Email:


The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only 
when there is a possibility for an award. It is anticipated that these 
changes will reduce the administrative burden for the applicants, reviewers 
and NIH staff.  The research grant application form PHS 398 (rev. 5/2001) at is to be used in 
applying for these grants, with the modifications noted below.  Applicants 
are permitted, however, to use the 4/1998 revision of the PHS 398 for 
scheduled application receipt dates until January 9, 2002.  If you are 
preparing an application using the 4/1998 version, please refer to the step-
by-step instructions for Modular Grants available at

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.
 Applications must be received by December 14, 2001. Applications not received 
as a single package on the receipt date or not conforming to the instructions 
contained in PHS 398 (rev. 5/01) Application Kit (as modified in, and 
superseded by, the special instructions below, for the purposes of this RFA) 
will be judged nonresponsive and will be returned to the applicant.
 If the application submitted in response to this RFA is substantially similar 
to a grant application already submitted to the NIH for review that has not 
yet been reviewed, the applicant will be asked to withdraw either the pending 
application or the new one.  Simultaneous submission of identical 
applications will not be allowed, nor will essentially identical applications 
be reviewed by different review committees.  Therefore, an application that 
is essentially identical to one that has already been reviewed cannot be 
submitted in response to this RFA.  This does not preclude the submission of 
substantial revisions of applications already reviewed, but such applications 
must include an introduction addressing the previous critique.
 Submit a signed, typewritten original of the application, including the 
checklist, and three signed, exact, single-sided photocopies in one package 
 Center for Scientific Review
 National Institutes of Health
 6701 Rockledge Drive, Room 1040 - MSC 7710
 Bethesda, MD  20892-7710
 Bethesda, MD  20817 (for express mail or courier service)
 At the time of submission, two additional exact copies of the grant 
application and all five sets of any appendix material must be sent to Dr. 
Tommy Broadwater at the address listed under INQUIRIES.
 Applicants from institutions that have a General Clinical Research Center 
(GCRC) funded by the NIH National Center for Research Resources may wish to 
identify the GCRC as a resource for conducting the proposed research.  If so, 
a letter of agreement from either the GCRC program director or principal 
investigator should be included with the application.
 Upon receipt, applications will be reviewed for completeness by the NIH 
Center for Scientific Review and for responsiveness by NIAMS staff; those 
judged to be incomplete or not in the format specified in this RFA will be 
returned to the applicant without review. Those considered to be 
nonresponsive will be returned without review.
 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 NIAMS in accordance with the review criteria stated below.  As 
part of the initial merit review, a process will be used by the initial 
review group in which all applications will receive a written critique but 
only those applications deemed to have the highest scientific merit will be 
discussed, assigned a priority score, and receive a second-level review by 
the National Advisory Council of the NIAMS. 
 Review Criteria
 The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  The 
reviewers will comment on the following aspects of the application in their 
written critiques 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 by the reviewers in assigning the 
overall score, weighting them as appropriate for each application.  Note that 
the application does not need to be strong in all categories to be judged 
likely to have a 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 
 1. 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?
 2. 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? 
 3. 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 
 4. 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)?
 5. 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?
 In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:
1. The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
2. The reasonableness of the proposed budget and duration in relation to 
the proposed research.
3. 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.
 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
 Inquiries concerning this RFA are encouraged. The opportunity to clarify any 
issues or questions from potential applicants is welcome. Direct inquiries 
regarding programmatic issues to:
 Elizabeth Gretz, Ph.D.
 Director, Immunology and Inflammation Program
 Rheumatic Diseases Branch
 National Institute of Arthritis and Musculoskeletal and Skin Diseases
 45 Center Drive, Natcher Bldg. Rm. 5A19J
 Bethesda MD 20892-6500
 Telephone: (301) 594-5032
 Fax: (301) 480-4543
 Deborah Ader, Ph.D.
 Director, Behavior and Prevention Research Program
 Rheumatic Diseases Branch
 National Institute of Arthritis and Musculoskeletal and Skin Diseases
 45 Center Drive, Natcher Bldg. Rm. 5A19H
 Bethesda MD 20892-6500
 Telephone: (301) 594-5032
 Fax: (301) 480-4543
 Direct review inquiries to:
 Tommy Broadwater, Ph.D
 Chief, Review Branch 
 National Institute of Arthritis and Musculoskeletal and Skin Diseases
 45 Center Drive, Natcher Bldg. Rm. 5A25U
 Bethesda, MD 20892-6500
 Telephone: (301) 594-4953
 Fax (301) 480-4543 
 Direct inquiries regarding fiscal matters to:
 Melinda Nelson
 Grants Management Officer
 National Institute of Arthritis and Musculoskeletal and Skin Diseases
 45 Center Drive, Natcher Bldg. Rm. 5A49F
 Bethesda, MD 20892-6500
 Telephone: (301) 594-3535
 Fax (301) 480-5450
 Letter of Intent Receipt Date:    November 2, 2001
 Application Receipt Date:         December 14, 2001
 Peer Review Date:                 March 2002
 Council Review:                   June 21, 2002
 Earliest Anticipated Start Date:  July 1, 2002
 This program is described in the Catalog of Federal Domestic Assistance No. 
93.846, Arthritis, Musculoskeletal and Skin Diseases Research.  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 and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  This 
program is not subject to the intergovernmental review requirements of 
Executive Order 12372 or Health Systems Agency review.
 The Public Health Service strongly encourages all grant and contract 
recipients to provide a smoke-free workplace and promote the non-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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