Release Date:  November 8, 2000

RFA:  AR-01-002

National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of Neurological Disorders and Stroke

Letter of Intent Receipt Date:  February 1, 2001
Application Receipt Date:       March 14, 2001



The National Institute of Arthritis and Musculoskeletal and Skin Diseases 
(NIAMS) and the National Institute of Neurological Disorders and Stroke 
(NINDS) invite exploratory and developmental research grant applications (R21) 
that will broaden the base of inquiry on Facioscapulohumeral muscular 
dystrophy (FSHD).


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 request for applications, 
Exploratory Research on Facioscapulohumeral Dystrophy, is related to the 
priority area chronic disabling conditions.  Potential applicants may obtain a 
copy of "Healthy People 2010" at http://www.health.gov/healthypeople/.


Applications may be submitted by domestic or foreign for-profit and non-profit 
organizations, public and private, such as universities, colleges, hospitals, 
laboratories, units of State and local governments, and eligible agencies of 
the Federal government.  Racial/ethnic minority individuals, women, and 
persons with disabilities are encouraged to apply as Principal Investigators. 
 Participation in the program by investigators at minority institutions is 
strongly encouraged.

Investigators who have questions about eligibility should contact one of the 
program officials listed under INQUIRIES.


Research projects will be supported with the exploratory/developmental 
research grant (R21).  The Exploratory/Developmental research mechanism (R21) 
is used for support of creative, novel, and/or high risk/high payoff 
approaches that could produce innovative advances in this field.  This 
includes feasibility studies, protocol planning, and the incorporation of new 
disciplines and technologies. This mechanism provides the means to acquire the 
necessary pilot information, to attract talented new investigators from 
related disciplines, and to foster the development of interdisciplinary, 
inter-institutional collaborative efforts among investigators with diverse 
training and expertise.  Applicants may request up to three years of support. 
 Applications for research at a single institution may request up to a maximum 
of $125,000 direct costs per year.  Applications that include a 
consortium/contractual arrangement may request up to a maximum of $150,000 
direct costs, including the facilities and administrative costs (indirect 
costs) of the consortium  institution.  These awards are not renewable.  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. 

This RFA is a one-time solicitation.  Responsibility for the planning, 
direction, and execution of the proposed project will be solely that of the 

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts.  Complete and detailed 
instructions and information on Modular Grants can be found at 


It is anticipated that for FY 2001, approximately $1.0 million total costs 
will be available for the first year of support for this RFA.  This funding 
level is dependent upon the receipt of a sufficient number of applications of 
high merit and on the availability of funds.  It is anticipated that up to 5 
new grants may be awarded in FY 2001 under this program.  Direct costs will be 
awarded in modules of $25,000.  Facilities and Administrative costs will be 
awarded based on the negotiated rates.  Applicants may request up to three 
years of support.



Facioscapulohumeral muscular dystrophy (FSHD) is the third most common genetic 
disease of skeletal muscle.  It affects approximately one in 20,000 persons.  
FSHD is an autosomal dominant disease that initially affects muscles of the 
face (facio), scapula (scapulo) and upper arms (humeral).  Symptoms may 
develop in early childhood and are usually noticeable in the teenage years 
with 95% of affected individuals manifesting disease by age 20 years.  A 
progressive skeletal muscle weakness usually develops in other areas of the 
body as well; often the weakness is asymmetrical.  Life expectancy is normal, 
but up to 15% of affected individuals become severely disabled and eventually 
must use a wheel chair.  Non-muscular symptoms frequently associated with FSHD 
include subclinical sensorineural hearing loss and retinal telangectasias.  
The pathophysiology of FSHD is not known.  Muscle histologic changes are non 
specific for the muscle wasting.  There is evidence of early inflammatory 
changes in the muscle, but reported responses to high dose open labeled 
corticosteroid treatment have been negative.  Animal studies of anabolic 
effects of beta adrenergic agonists on models of muscle wasting led to an open 
trial of albuterol (a beta adrenergic agonist) in which limited preliminary 
results support an improvement of muscle mass and strength in FSHD.  
Preliminary studies of muscle cultures suggest an increased sensitivity to 
oxidative stress, but require further exploration. 

More than 95% of cases of FSHD are associated with the deletion of integral 
copies of a tandemly repeated 3.3kb unit (D4Z4 repeat) at the subtelomeric 
region 4q35.  Inheritance is autosomal dominant, though up to one-third of the 
cases appear to be the result of de novo (new) mutations. The deletion appears 
to result in global dislocation of gene expression.  If the entire region is 
removed, there are birth defects, but no specific defects on skeletal muscle. 
Individuals appear to require the existence of 11 or fewer repeat units to be 
at risk for FSHD.  Though the nature of the DNA mutation is known, it has not 
been possible to identify a gene or mechanism that causes FSHD and a novel 
position effect has been postulated to explain the disease phenotype.  In 
addition, some cases of FSHD are the result of rearrangements between 
subtelomeric chromosome 4q and a subtelomeric region of 10q that contains a 
tandem repeat structure highly homologous (95%) to 4q35.  Disease occurs when 
the translocation results in a critical loss of tandem repeats to the 4q site. 
 Finally, there is a large family with a phenotype indistinguishable from FSHD 
in which no pathological changes at the 4q site or translocation of 4q-10q are 

NIAMS and NINDS sponsored a conference on FSHD in May 2000.  This was followed 
by a brief session in which researchers considered possible approaches for 
increasing knowledge about the pathogenesis and treatment of the disease.  A 
brief summary may be seen at: http://www.nih.gov/niams/reports/fshdsummary.htm

Scope and Objectives:

The NIAMS and NINDS seek to broaden the base of knowledge concerning the 
pathogenesis of FSHD and possible therapies by encouraging exploratory 
research.  Because exploratory  projects may require a preliminary test of 
feasibility, this initiative will provide short-term support for such 
preliminary work.  Each research plan should begin with a short paragraph 
describing the feasibility of the approach to increase knowledge about disease 
pathogenesis and disease processes that might be ameliorated. 

Applications in response to this RFA should address issues related to 
characterizations and pathogenesis of FSHD.  Examples of areas included in 
this RFA are listed below.

o  Characterize the molecular pathogenesis of FSHD and elucidate the role of 
the 3.3 kilobase tandem repeats in maintaining of heterochromatin structure 
and the mechanism of tandem repeat deletions in this critical region of 4q.

o  Determine the relationship between repeat length and its effect on 
penetrance.  Determine also whether the loss of certain repeats is always 
associated with FSHD clinical expression, since there may be specificity in 
chromosomal transactions and the resulting pathogenesis.

o  Determine the gene sequence and whether the repeats are acting as 
suppressors or insulating units.  The region containing the site associated 
with at least 95% of FSHD cases is composed almost entirely of the 3.3 
kilobase repeats, which are not translated.  Few genes have been found near 
the multi-repeat locus, suggesting that FSHD may result from alterations in 
the chromatin structure.  In particular, the data suggest that you need a 
minimum size of repeats in order to have a compact heterochromatin structure.

o  Clarify how similarity of regions on chromosomes 4 and 10 may relate to 
FSHD.  There is a region on chromosome 10 that appears to be largely identical 
(95% homology) to that on chromosome 4 at the FSHD locus (4q35).  Studies on 
affected and unaffected populations show that there is a high amount of 
exchange between the homologous regions on chromosomes 4 and 10.  Although 
disease has never been associated with alterations on chromosome 10, the 
frequency of such exchanges may be related to the high proportion of new 
(i.e., non-familial) cases of FSHD encountered.

o  Characterize changes in muscle as the disease develops.  This would be 
facilitated by non-invasive ways of looking at the muscle and microvasculature 
in affected and non-symptomatic regions.  Studies using improved imaging 
techniques would provide better assessment of patient muscle, including 
vasculature, that is pre-atrophic. 

o  Determine basis of differential involvement of muscles, reflected by the 
regional pattern of disease.  Comparison of muscle groups might show the cause 
of relative specificity of affected muscles.  Comparing expression patterns of 
RNA and protein in affected and non-affected muscle will provide insights into 
alterations occurring as the disease progresses. 

o  Explore the role of inflammation in FSHD.  While FSHD has been described as 
the most inflammatory form of muscular dystrophy, there is no evidence that 
disease severity is lessened by administration of the anti-inflammatory drug 
prednisone.  It is necessary to explore the relationship between inflammatory 
cells, muscle cell death, and blood vessels. 

o  Study properties of muscle cells derived from affected tissue. Cells 
cultured from FSHD muscle show increased sensitivity to oxidative stress.  
This needs to be followed up by studies verifying that this occurs in vivo and 
establishing how this cellular phenotype develops. 

o  Determine if a nonstandard locus produces FSHD.  Characterize the gene 
defects in the family with FSHD phenotype but no linkage to the 4q35 locus to 
pursue a better understanding of FSHD disease processes.

o  Create new models of FSHD.  The development of new models of the genetic 
pathogenesis of FSHD would provide a tool to research scientists in muscle 
biology, attracting new investigations to pursue understanding of disease 
pathogenesis and eventual therapies for FSHD.


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 
(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.

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 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:  https://grants.nih.gov/grants/guide/notice-files/not98-024.html.

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. 


Prospective applicants are asked to submit, by February 1, 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, 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 NIH 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.


The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants, with the modifications noted below.  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

The RFA label found in the PHS 398 (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application.  The RFA label and 
line 2 of the application should both indicate the RFA number.  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.

For purposes of identification and processing, item 2a on the face page of the 
application must be marked "YES" and the RFA number "AR-01-002" and the words 
face page.


Modular grant applications that include a consortium/contractual arrangement 
may request direct costs in $25,000 modules up to a yearly maximum of $150,000 
direct costs, including the facilities and administrative costs (indirect 
costs) for the consortium institution.  Applications proposing research at a 
single institution may request up to a maximum of $125,000 direct costs per 

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

o  FACE PAGE - Items 7a and 7b should be completed, indicating Direct Costs 
(in $25,000 increments up to a maximum of $125,000 for research at a single 
institution, or up to a maximum of $150,000 for research involving a 
consortium/contractual arrangement) 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.

of the PHS 398.  It is not required and will not be accepted with the 

categorical budget table on Form page 5 of the PHS 398.  It is not required 
and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION - Use 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. 
o  Under Personnel, list all project personnel, including their names, percent 
of effort, and roles on the project.  No individual salary information should 
be provided.

o  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 all 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.  

o  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:  

-  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;
-  List selected peer-reviewed publications, with full citations.

o  CHECKLIST - This page should be completed and submitted with the 
application.  If the 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.

o  PAGE LIMITATION - In keeping with the pilot/feasibility nature of the 
requested studies the application (aims, background and significance, 
preliminary data and experimental design and methods) is limited to 20 pages. 
Tables and figures are included in the 20-page limitation.

o  APPENDIX - An appendix or additional supporting materials will not be 
accepted with the exception of originals of photos used in the application.  

o  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.


Submit a signed typewritten original of the application and three signed 
photocopies, in one package to:

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:

Tommy L. Broadwater, Ph.D.
Scientific Review Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-25U - MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-4952
FAX: (301)-402-2406
Email: broadwat@exchange.nih.gov

In order not to delay review, it is important that applicants comply with this 

Applications must be received by March 14, 2001.  If an application is 
received after that date, it will be returned to the applicant without review. 
Only one R21 grant application may be submitted by a Principal Investigator.


Upon receipt, applications will be reviewed for completeness by CSR and 
responsiveness by NIAMS and NINDS.  Incomplete and/or non-responsive 
applications will be returned to the applicant without further consideration. 
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 receive a written critique and 
under 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, assigned a priority score, and receive a second level 
review by the appropriate national 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.  For 
this initiative, the proposed project must have the potential for developing 
approaches or information that may lead to significant increases in 
understanding or treating FSHD.  In the written review, comments on the 
following aspects of the application will be made 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 in the assignment of the overall score.

(1) Significance.  Does this study address issues important to understanding 
and treating FSHD?  If the aims of the application are achieved, how will 
scientific knowledge about FSHD be advanced?  What will be the effect of these 
studies on the concepts or methods that drive research on FSHD? 

(2) Approach.  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the investigator acknowledge potential problem areas and 
consider alternative tactics?

(3) Innovation.  Does this application have the potential for ground breaking 
advances that may lead to new approaches to research on FSHD?   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?  If the project is not innovative but is 
essential to move the field forward, the applicant should mention and discuss 
this aspect in the proposal.

(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 

The initial review group will also examine the provisions for the protection 
of human and animal subjects, the safety of the research environment, and 
conformance with the NIH Guidelines for the Inclusion of Women, Minorities and 
their subgroups, and children as Subjects in Clinical Research.

The personnel category will be reviewed for appropriate staffing based on the 
requested percent effort.  The direct costs budget request will be reviewed 
for consistency with the proposed methods and specific aims.  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. 


The following will be considered in making funding decisions:

o  Scientific merit of the proposed project as determined by peer review;
o  Importance of the area to understanding and treating FSHD;
o  Potential for ground breaking advances that may lead to new approaches to 
research on FSHD; and  
o  Availability of funds.


Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic and scientific issues to one of the 
following persons: 

Richard W. Lymn, Ph.D.
Muscle Biology Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-49E
Bethesda, MD  20892-6500
Telephone:  (301) 594-5128
FAX:  (301) 480-4543
Email: LymnR@mail.nih.gov

Giovanna M. Spinella, M.D.
Division of Fundamental Neuroscience and Developmental Disorders
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 2132
Bethesda, MD  20892
Telephone:  (301) 496-5745
FAX:  (301) 402-0887
Email:  gs41b@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) 594-4952
FAX (301) 480-4543 
Email: broadwat@exchange.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, Room 5AS-49F, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-3535
FAX:  (301) 480-5450
Email:  nelsonm@mail.nih.gov

Karen D. Shields
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3264
Bethesda, MD  20892
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  ks26n@nih.gov


This program is described in the Catalog of Federal Domestic Assistance No. 
93.846 (NIAMS) and  No. 93.853 (NINDS).  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 PHS 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 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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