MOLECULAR PATHOGENESIS AND NEW INTERVENTIONS IN SCLERODERMA

Release Date:  September 12, 2000

RFA:  AR-00-007

National Institute of Arthritis and Musculoskeletal and Skin Diseases
Office of Research of Women's Health

Letter of Intent Receipt Date:  October 1, 2000
Application Receipt Date:       December 15, 2000

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE

The goal of this Request for Applications (RFA) is to foster developmental and 
traditional research projects to advance our understanding of the pathogenesis 
of scleroderma and to promote the design, development and pilot testing of 
hypothesis-driven innovative therapeutic approaches.  Systemic sclerosis 
(scleroderma) is a chronic condition characterized by the progressive 
thickening of the skin and involvement of internal organs, most notably the 
heart, kidneys, lungs and digestive tract.  This RFA is based in part on the 
scientific opportunities identified in the conference "Emerging Opportunities 
in Scleroderma Research".  A summary of the conference and research questions 
raised can be found at http://www.nih.gov/niams/reports/sclersum.htm.

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 several 
objectives, particularly those listed in the chapter "Arthritis, Osteoporosis, 
and Chronic Back Conditions".  Potential applicants may obtain "Healthy People 
2010" at http://www.health.gov/healthypeople. 

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit 
organizations, public or private, such as universities, colleges, hospitals, 
laboratories, units of state and local governments, and eligible agencies of 
the Federal government.  Foreign institutions are not eligible to apply for 
these grants, however, applicants 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.  

MECHANISM OF SUPPORT

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

R21 Applications.  Use of this mechanism is recommended for investigators 
experienced in scleroderma research who wish to adapt new methods or 
techniques established in other fields to develop scientific approaches and 
models to study the pathogenesis and gather pre-clinical data of new therapies 
or preliminary data on toxicity and potential efficacy in a limited number of 
patients.  Investigators with expertise in fields other than scleroderma who 
wish to establish new research programs on the disease are also encouraged to 
use this mechanism.

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.  If desired, the specific aims of the R21 project 
may be incorporated into a research project grant application (R01) submitted 
prior to the termination of the R21 award. 

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).

Investigators who wish to establish new collaborative research programs with 
intramural laboratories at the NIAMS, and apply for funding under this RFA, 
are encouraged to contact Dr. Barbara Mittleman, Director of Scientific 
Interchange, NIAMS (mittlemb@mail.nih.gov).
 
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 
https://grants.nih.gov/grants/funding/modular/modular.htm.

FUNDS AVAILABLE

It is anticipated that for FY 2001 approximately $1.5 million total costs will 
be available for the first year of support for this initiative.  Award of 
grants is contingent upon the receipt of such funds for this purpose.  The 
specific number to be funded will depend on the merit and scope of the 
applications received and the availability of funds.  Applicants may request 
up to five years of support for the R01.  Direct costs will be awarded in 
modules of $25,000, less any overlap or other necessary administrative 
adjustments.  Facilities and Administrative costs will be awarded based on the 
negotiated rates.   

Exploratory/developmental (R21) grants, may not exceed $75,000 per year in 
direct costs, including indirect costs for collaborating institutions, if any. 
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.

RESEARCH OBJECTIVES

The pathogenesis of scleroderma is complex and not well understood.  Immune 
activation, vascular abnormalities and dysregulation of extracellular matrix 
components contribute to end stage obliterative vasculopathy and fibrosis.  
Host and environmental factors may contribute to disease predisposition and 
onset. Although these disease components have been known for some time, their 
roles in disease initiation and progression are unclear. Research efforts in 
scleroderma have been focused on the analysis of the immune abnormalities with 
emphasis on the molecular characterization of autoantibodies specificity, and 
more recently on autoreactive T cells and cytokine production.  Another major 
research focus has been on the analysis of abnormal collagen production and 
the regulatory molecular pathways that control collagen production by 
fibroblasts. Recently, however, new clues point to host factors related to 
immune activation and regulation of endothelial cell activity as potentially 
key early events in the pathogenesis of scleroderma.  

A group of scleroderma researchers and experts in other relevant fields was 
convened in December of 1997 to explore the new and emerging research findings 
in scleroderma, 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/sclersum.htm.

The purpose of this announcement is to encourage pilot and developmental  
projects (R21) and investigator initiated research projects (R01) that explore 
new approaches and hypotheses on the pathogenesis of scleroderma.  In 
addition, the initiative also seeks to promote the development and pilot 
testing of new therapeutic approaches, including alternative and complementary 
medicine. Potential areas of research include, but are not limited to:

o the role of apoptosis-related molecules and other intracellular events 
in fibroblasts, immune and endothelial cells in scleroderma; 

o the role and regulation of oxygen radicals and other mediators of local 
tissue injury in skin and other organ involvement;

o the role of microchimerism in the induction of local tissue changes, and 
systemic and  local immune dysregulation; 

o the study of genes that may contribute to disease onset or 
manifestations; 

o studies on the regulation of synthesis, structure,  function and 
clearance of  molecular components of the extracellular matrix (ECM);

o analysis of  interactions between ECM and immune cells;

o the study of molecular and cellular events in the vascular wall that 
contribute to reactivity and vasculopathy; 

o mechanisms of induction of injury and repair of organs involved in the 
disease;	

o therapies that control ECM metabolism;

o pharmacologic and alternative approaches leading to reduction of GI 
symptoms and tissue injury;

o new approaches to reduce progressive lung disease;

o new animal model systems to dissect disease pathogenesis and test new 
therapies;

o studies designed to explore the molecular and/or genetic basis for sex, 
gender and ethnic disparities; and

o clinical research studies on biomarkers and new diagnostic 
methodologies.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

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 biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are 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 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 
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at  
https://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  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.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of 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 
dated 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: 
https://grants.nih.gov/grants/guide/notice-files/not98-024.html.

Investigators may also obtain copies of these policies from the program staff 
listed under INQUIRIES. Program staff may also provide additional relevant 
information concerning the policy.

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.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

LETTER OF INTENT

Prospective applicants are asked to submit, by October 1, 2000, 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, is not binding, does 
not commit the sender to submit an application, 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 avoid conflict of interest 
in the review.  The letter of intent is to be sent (e-mail, fax or post) to 
Dr. Tommy Broadwater at the address listed under INQUIRIES.

APPLICATION PROCEDURES

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 
Institute staff.  The Research Grant Application Form PHS 398 (rev. 4/98), 
with the modifications noted below, is to be used in applying for these 
grants.

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up to 
a total direct cost request of $250,000 per year. Applications that request 
more than $250,000 direct costs in any year must follow the traditional PHS 
398 application instructions. The total direct costs must be requested in 
accordance with the program guidelines and the modifications made to the 
standard PHS 398 application instructions described below:

PHS 398

FACE PAGE - Items 7a and 7b should be completed, indicating Direct Costs 
(in $25,000 increments up to a maximum of $250,000) and Total Costs 
[Modular Total Direct plus Facilities and Administrative  (F&A) costs] 
for the initial budget period, and Items 8a and 8b should be completed 
indicating the Direct and Total Costs for the entire proposed period of 
support.

DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form 
Page 4 of the PHS 398.  It is not required and will not be accepted with 
the application.

BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the 
categorical budget table on Form Page 5 of the PHS 398. It is not 
required and will not be accepted with the application.

NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget 
Narrative page. (See 
https://grants.nih.gov/grants/funding/modular/modular.htm for sample 
pages.) At the top of the page, enter the total direct costs requested 
for each year.  This is not a Form page.

Under Personnel, list all project personnel, including their names, 
percent of effort, and roles on the project. No individual salary 
information should be provided.  However, the applicant should use the 
NIH appropriation language salary cap and the NIH policy for graduate 
student compensation in developing the budget request.

For Consortium/Contractual costs, provide an estimate of total costs 
(direct plus facilities and administrative) for each year, each rounded 
to the nearest $1,000.  List the individuals/organizations with whom 
consortium or contractual arrangements have been made, the percent 
effort of key personnel, and the role on the project. Indicate whether 
the collaborating institution is foreign or domestic.  The total cost 
for a consortium/contractual arrangement is included in the overall 
requested modular direct cost amount.  Include the Letter of Intent to 
establish a consortium.

Provide an additional narrative budget justification for any variation 
in the number of modules requested.

BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used 
by reviewers in the assessment of each individual's qualifications for a 
specific role in the proposed project, as well as to evaluate the 
overall qualifications of the research team.  A biographical sketch is 
required for all key personnel, following the instructions below.  No 
more than three pages may be used for each person. A sample biographical 
sketch may be viewed at 
https://grants.nih.gov/grants/funding/modular/modular.htm.

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
  research projects ongoing or completed during the last three years;   
  and
- List selected peer-reviewed publications, with full citations.

RESEARCH PLAN B The research plan (a-d) is limited to 20 pages for R01s 
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.

CHECKLIST - This page should be completed and submitted with the 
application. If the facilities and administration (F&A) rate agreement 
has been established, indicate the type of agreement and the date. All 
appropriate exclusions must be applied in the calculation of the F&A 
costs for the initial budget period and all future budget years.

The applicant should provide the name and phone number of the individual 
to contact concerning fiscal and administrative issues if additional 
information is necessary following the initial review. 

Applications are to be submitted on the Grant Application Form PHS 398 (rev. 
4/98). These forms are available at most institutional offices of sponsored 
research; from the Division of Extramural Outreach and Information Resources, 
National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 
20892-7910, telephone 301/710-0267, email: grantsinfo@nih.gov; and on the 
internet at https://grants.nih.gov/grants/funding/phs398/phs398.html.

For purposes of identification and processing, item 2a on the face page of the 
application must be marked "YES" and the RFA number "AR-00-007" and the words 
"MOLECULAR PATHOGENESIS AND NEW INTERVENTIONS IN SCLERODERMA" must be entered 
on the face page.

The RFA label and line 2 of the application should both indicate the RFA 
number.  The RFA label must be affixed to the bottom of the face page.  
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.

The sample RFA label available at 
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to 
allow for this change.  Please note this is in pdf format.

Applications must be received by December 15, 2000.  Applications not received 
as a single package on the receipt date or not conforming to the instructions 
contained in PHS 398 (rev. 4/98) Application Kit (as modified in, and 
superseded by, the special instructions below, for the purposes of this RFA), 
will be judged non-responsive and 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, but 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.

An application in response to this RFA may be of interest to the National 
Heart, Lung, and Blood Institute (NHLBI) and possible assignment to that 
Institute will be considered on a case-by-case basis depending on the 
objectives of the study.

Submit a signed, typewritten original of the application, including the 
checklist, and three signed, exact, single-sided 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 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.

REVIEW CONSIDERATIONS  

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 non-responsive 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 
Arthritis and Musculoskeltal and Skin Diseases Advisory Council.

REVIEW CRITERIA

The five criteria to be used in the evaluation of grant applications are 
listed below.  To put those criteria in context, the following information is 
contained in instructions to the peer reviewers.

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 forward.

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 
method?  Are the aims original and innovative?  Does the project 
challenge existing paradigms or develop new methodologies or 
technologies? 

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:

o 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 evaluated.

o The reasonableness of the proposed budget and duration in relation to 
the proposed research

o 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

The personnel category will be reviewed for appropriate staffing based on the 
requested percent of effort.  The direct costs budget request will be reviewed 
for consistency with the proposed methods and specific aims. For modular grant 
applications, any budgetary adjustments recommended by the reviewers will be 
in $25,000 modules.  The duration of support will be reviewed to determine if 
it is appropriate to ensure successful completion of the requested scope of 
the project.

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

INQUIRIES

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:

Susana Serrate-Sztein, M.D.
Rheumatic Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Natcher Bldg. Rm. 5A25
Bethesda Md 20892-6500
Telephone: (301) 594-5032
FAX (301) 480-4543
Email: szteins@mail.nih.gov

Direct review inquiries to:

Tommy Broadwater, Ph.D.
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 
Email: broadwatert@mail.nih.gov

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. 5A49
Bethesda Md 20892-6500
Telephone: (301) 594-3535
FAX (301) 480-5450
Email: mn23z@nih.gov

Schedule:

Letter of Intent Receipt Date:    October 1, 2000
Application Receipt Date:         December 15, 2000
Peer Review Date:                 March 2001
Council Review:                   June 2001
Earliest Anticipated Start Date:  July 2001

AUTHORITY AND REGULATIONS
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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