THERAPEUTIC AND PATHOGENIC APPROACHES FOR THE MUSCULAR DYSTROPHIES

Release Date:  January 4, 2001

PA NUMBER:  PAS-01-041 (This PAS has been reissued, see PA-05-038)

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

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

PURPOSE

The National Institute of Arthritis and Musculoskeletal and Skin Diseases 
(NIAMS) and the National Institute of Neurological Disorders and Stroke 
(NINDS) encourage investigator-initiated research grant applications of 
therapeutic and pathogenic approaches for the muscular dystrophies.  
Responses to this program announcement may include studies in appropriate 
animal models or preclinical or clinical studies in patients with Duchenne 
muscular dystrophy (DMD), Becker muscular dystrophy (BMD), 
facioscapulohumeral dystrophy (FSHD), limb-girdle muscular dystrophy (LGMD), 
myotonic dystrophy (DM), congenital muscular dystrophy (CMD), Emery-Dreifuss 
muscular dystrophy (EMD), or other forms of muscular dystrophy. 

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 PA is related to one 
or more of the priority areas.  This program announcement, Therapeutic and 
Pathogenic Approaches for the  Muscular Dystrophies, 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/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and 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.

MECHANISM OF SUPPORT
The mechanisms of support will be the individual research project grant (R01) 
and the program project grant (P01).  The Principal Investigator or program 
director, as well as any participating investigators, will plan, direct, and 
perform the research.  The total project period for an application submitted 
in response to this program announcement may not exceed five years.

For all competing individual research project grant (R01) applications 
requesting up to $250,000 direct costs per year, specific application 
instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" 
streamlining efforts being examined by NIH.  Complete and detailed 
instructions and information on Modular Grant applications can be found at:  
http://grants.nih.gov/grants/funding/modular/modular.htm.  Applications that 
request more than $250,000 in any year must use the standard PHS 398 (rev. 
4/98) application instructions.

Applicants must receive permission from the NIAMS or NINDS prior to the 
submission of an application requesting more than $500,000 in direct costs 
per year for any year of the proposed study.  In addition, applications for 
program project grants may only be submitted from domestic organizations and 
investigators are requested to contact the NIAMS or NINDS representative 
listed under INQUIRIES as early as possible in the planning stages.

FUNDS AVAILABLE

NIAMS and NINDS intend to commit approximately $ 5.0 million in total costs 
to fund competing applications submitted in response to this announcement 
during fiscal years 2002- 2004.  Although the financial plans of NIAMS and 
NINDS provide support for this program, awards pursuant to this PA are 
contingent upon availability of funds and the receipt of a sufficient number 
of meritorious applications.

RESEARCH OBJECTIVES

Background

Muscular dystrophies collectively have a high impact on health, affecting 
tens of thousands of people in the United States alone.  The diseases are 
characterized by weakness and wasting of muscles.  Many incidents of muscular 
dystrophy represent new occurrences of disease, where there is no prior 
family history.  Though research has recently revealed much about genetic 
defects associated with many forms of muscular dystrophy, treatment for the 
diseases has not changed significantly.  There is a need to learn more about 
pathogenesis of the diseases and ways to treat affected people.

Duchenne muscular dystrophy (DMD) is most common, affecting approximately one 
in 3,500 male births.  This X-linked disease is characterized by muscle 
necrosis and regeneration.  The regenerative process cannot maintain normal 
muscle tissue and mass, resulting in progressive muscle fiber loss.  Affected 
boys usually must use wheelchairs by age 12, with death often occurring by 
age 20 from cardiac or respiratory problems.  The genetic defect leads to 
missing or abnormal dystrophin, an important structural protein unknown until 
the gene was discovered.  A milder variant, Becker muscular dystrophy (BMD), 
is caused by different defects in the DMD gene, that produce truncated but 
partially functional dystrophin.  Symptoms are similar to DMD, with muscles 
of the pelvis, upper arms, and upper legs affected first, but they are more 
variable than in DMD.  Some affected individuals are able to walk only until 
early adulthood, others to an advanced age.  Survival in some is to middle 
age but others have survived more than 80 years.  Heart trouble may develop 
in early adulthood.  The National Institute of Neurological Disorders and 
Stroke, the National Institute of Arthritis and Musculoskeletal and Skin 
Diseases and the Office of Rare Diseases sponsored a workshop on the 
Therapeutic Approaches for Duchenne Muscular Dystrophy (DMD), May 15-16, 2000 
in Bethesda, MD.  The goals of this workshop were to address key questions in 
improving treatments for DMD and identify areas of needed scientific 
knowledge, impediments, and critical next steps to promote effective therapy.  
A summary of the workshop may be found at: 
http://www.ninds.nih.gov/news_and_events/proceedings/dmdmtngsummary.htm

Myotonic dystrophy (DM) is the most common form of muscular dystrophy in 
adults.  It is dominantly inherited and, in addition to skeletal muscles, 
affects the brain, the lens of the eye, and the heart.  Myotonic dystrophy is 
one of the growing number of triplet repeat disorders, it is associated with 
a CGT expansion in an untranslated region of 19q13.3.  Larger numbers of 
repeats are found in more severely affected individuals, and the number of 
repeats tends to increase from generation to generation, thus explaining 
earlier age of onset and increased symptoms in subsequent generations 
(anticipation).  The product of the myotonic dystrophy locus on chromosome 19 
is a novel form of protein kinase.  The function of this specific kinase is 
unknown, and it has yet to be determined whether a defect in this protein 
leads to the myotonic dystrophy phenotype.

Facioscapulohumeral (FSH) muscular dystrophy is an autosomal dominant form 
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.  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 some affected 
individuals become severely disabled.  Nearly all cases are associated with a 
distal 4q35 deletion.  Because there are no known genes in this region, a 
novel position effect has been postulated to explain the disease phenotype.  
The National Institute of Arthritis and Musculoskeletal and Skin Diseases, 
the National Institute of Neurological Disorders and Stroke, and the Office 
of Rare Diseases sponsored a Conference on the Cause and Treatment of 
Facioscapulohumeral Muscular Dystrophy, held in Bethesda, MD on May 8-9, 
2000.  A summary of this meeting may be found at: 
http://www.nih.gov/niams/reports/fshdsummary.htm.

The limb-girdle muscular dystrophies (LGMD) are genetically heterogeneous, 
with both dominant and recessive forms reported.  All limb-girdle muscular 
dystrophies show a similar distribution of muscle weakness, affecting both 
upper arms and legs.  The recessive LGMDs are more frequent than the dominant 
forms, and usually have a childhood or teen-age onset.  The dominant LGMDs 
usually show an adult onset.  In addition to muscle weakness, the creatine 
kinase (CK) values are elevated in affected individuals, usually 4-10 times 
the normal laboratory values.  Four of the recessive forms have been 
associated with defects in genes coding for the sarcoglycan complex, which, 
along with dystrophin, helps anchor muscles to the extracellular matrix.  
More devastating mutations in these same genes can cause severe childhood 
autosomal muscular dystrophy (SCARMD).

Emery-Dreifuss muscular dystrophy (EMD) is a sex-linked form characterized by 
wasting of shoulder, upper arm, and shin muscles.  Joint deformities are 
common.  It also inflicts serious cardiac problems that can result in 
premature and sudden death.  Cardiac involvement may also cause premature 
death in female carriers.  The responsible sex-linked gene has been located 
(Xq28), and it has been found to code for a previously unknown protein, 
called emerin, associated with the muscle membrane.  Emerin is normally found 
in both skeletal and heart muscle.  Different mutations of this gene may 
result in the absence of emerin and thus the disease.  A few cases have been 
found in which emerin is normal, suggesting genetic heterogeneity.

Congenital muscular dystrophy (CMD) is a heterogeneous group of severe 
autosomal-recessive neuromuscular diseases with early clinical onsets.  
Manifestations of CMD are evident at birth or in the first few months of life 
and consist of muscle weakness and hypotonia, delayed motor milestones, 
severe and early contractures, and, often, joint deformities.  Some cases of 
CMD have been attributed to absence of merosin, a component of laminin.  
Laminin is the extracellular component of the complex that, together with 
dystrophin and associated glycoproteins, anchors the muscle cell.  The same 
gene is responsible for one of the animal models of muscular dystrophy, the 
dy/dy mouse.

Although genes responsible for many forms of muscular dystrophy have been 
identified, much more research is needed to discover the pathogenic 
mechanisms involved and develop effective treatments.  

Scope and Objectives

A principal goal of this initiative is to promote research that will lead to 
better treatment for the muscular dystrophies.  The NIAMS and NINDS encourage 
investigator-initiated research grant applications to study therapeutic and 
pathogenic approaches.  Important research priorities  include studies on 
gene and stem cell therapies,  pharmacological approaches to treatment, and 
clarification of the role of inflammatory mechanisms.  

Responses to this program announcement may include studies in appropriate 
animal models or preclinical or clinical studies in patients.  Investigators 
with diverse scientific interests are invited to apply their expertise to 
basic, applied, and clinical research to enhance our understanding of the 
pathogenesis and treatment of the muscular dystrophies, including the 
development and sharing of appropriate resources, including animal models. 

Examples that illustrate possible areas of research are presented below.  
They are intended only to provide a broad direction for research and should 
be considered illustrative and not restrictive.  Special emphasis is on areas 
discussed in the reports of the recent meetings held at the NIH on DMD and 
FSHD.

The following general examples are relevant to several forms of muscular 
dystrophy:

o  examine genetic heterogeneity, and search for additional candidate genes, 

o  examine genotype/phenotype correlations within and between families,

o  develop improved diagnostic procedures,

o  improve imaging techniques to better diagnose and monitor muscle disease,

o  study pathogenic mechanisms leading from gene defects to muscular 
dystrophy phenotypes,

o  clarify the role of inflammatory changes that accompany tissue 
degeneration,

o  explore further development of new types of therapy, including gene 
transfer and gene correction, 

o  study muscle stem cells and their therapeutic possibilities,

o  explore pharmacologic interventions: evaluate current use of steroids,

o  further pursue the development and sharing of appropriate animal models 
for muscular dystrophies,

o  study the involvement of apoptotic cell death in the process of muscle 
fiber degeneration, and

o  improve therapeutic value of protein expression from transplanted 
myoblasts.

Several examples of research needs in DMD, taken from the May 2000 meeting, 
are:

o  characterize molecular aspects of the Duchenne muscular dystrophy 
population,	

o  clarify the role of inflammatory changes that accompany tissue 
degeneration,	

o  study the nature of the inflammatory changes that accompany degeneration 
in DMD,

o  determine if the dystrophin-glycoprotein complex has both a mechanical and 
signaling role, 

o  examine the role of dystrophin-glycoprotein disruption in tissues other 
than striated muscle, such as retina, brain, and vascular tissues, 	

o  improve techniques for possible gene transfer therapies, by optimizing the 
expression cassette, improving the design of viral vectors, clarifying and 
managing immunologic consequences, and optimizing gene delivery in terms of 
tissue targeting and efficiency of transfecting cells,

o  expand studies on alternative (non-viral) approaches that target the 
endogenous dystrophin gene (gene correction through the use of chimeraplasts, 
exon skipping and mRNA splicing through the use of antisense 
oligonucleotides, and alteration of translation by suppression of stop codons 
through the use of aminoglycoside antibiotics),

o  expand the use of muscle stem cells for possible therapy, through 
clarifying their origin and developmental state, find ways to identify and 
purify muscle stem cells, improve conditions for culturing and expanding cell 
populations, determine if stem cells can be delivered through the circulatory 
system efficiently and effectively, and

o  explore pharmacological therapeutic approaches, including the role of 
anti-inflammatory agents, and determine mechanisms of action.

Several examples of research needs in FSHD, taken from the May 2000 meeting, 
are:

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. 

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 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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), 
a complete copy of the updated Guidelines is available at 
http://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 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:  http://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. 

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.

APPLICATION PROCEDURES

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 301/435-0714, Email: grantsinfo@nih.gov, and on the internet 
at http://grants.nih.gov/grants/funding/phs398/phs398.html.  Applications should 
be submitted at the standard times indicated in the application instructions.

Applicants planning to submit an investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended/revised 
version of the preceding grant application types requesting $500,000 or more 
in direct costs for any year are advised that he or she must contact the 
Institute or Center (IC) program staff before submitting the application, 
i.e., as plans for the study are being developed.  Furthermore, the 
application must obtain agreement from the IC staff that the IC will accept 
the application for consideration for award.  Finally, the applicant must 
identify, in a cover letter sent with the application, the staff member and 
Institute or Center who agreed to accept assignment of the application.  This 
policy requires an applicant to obtain agreement for acceptance of both any 
such application and any such subsequent amendment.  Refer to the NIH Guide 
for Grants and Contracts, March 20, 1998 at 
http://grants.nih.gov/grants/guide/notice-files/not98-030.html

Applicants for the program project grant (P01) should contact the NIAMS and 
NINDS program officers listed under INQUIRIES to discuss their planned 
projects and to request the Institute"s guidelines for program project 
applications.  Guidelines may be found at: 
http://www.nih.gov/niams/grants/Guidelines/guidelines.htm (NIAMS) and 
http://www.ninds.nih.gov/funding/ppg_guidelines.htm (NINDS). 

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

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

o 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 Items 8a and 8b should be completed indicating the Direct and 
Total Costs for the entire proposed period of support.

o 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.

o 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.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
page. (See http://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.

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. 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 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:  
http://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.
- 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 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. 

GENERAL INSTRUCTIONS

Check "YES" in item 2a on the face sheet of the application and type 
 Therapeutic and Pathogenic Approaches for the  Muscular Dystrophies. 

Submit a signed, typewritten original of the application, including the 
Checklist, plus five 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)

If the application is for a program project, submit the original and three 
copies to the Center for Scientific Review.  An additional two copies must be 
sent to the program director for the institute that has agreed to accept, 
either Dr. Lymn or Dr. Spinella, at the addresses listed under INQUIRIES to 
expedite processing and review of applications for multi disciplinary 
efforts. 

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established referral 
guidelines.  Applications that are complete will be evaluated for scientific 
and technical merit by an appropriate scientific peer review group convened 
in accordance with NIH peer review procedures.  As part of the initial merit 
review, all applications will receive a written critique and undergo a 
process in which 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 assigned 
Institute(s).

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written 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.  
Note that 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.

o  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?

o  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?

o  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 technologies?

o  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)? 

o  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.

o  Review of grants with foreign components will consider availability of 
special opportunities for furthering research programs through the use of 
unusual talent resources, populations, or environmental conditions in other 
countries which are not readily available in the United States or which 
provide augmentation of existing United States resources.

o  For program project grant applications, additional factors to be 
considered during the review would include the efficacy of the collaboration, 
the commitment of the participants to the collaboration, the design and 
responsibilities of the coordinating center and the cost effectiveness of the 
collaborative effort.

AWARD CRITERIA

Applications will compete for available funds within the annual set-aside 
mentioned under FUNDS AVAILABLE.  Beyond the limits of the set-aside 
applications will compete with all other approved applications.  The 
following will be used in making funding decisions: 

o  Scientific and technical merit of the proposed project as determined by 
peer review

o  Availability of funds

o  Program balance among research areas of the announcement 

NIAMS funding policy may be seen at: 
http://www.nih.gov/niams/grants/payline2.htm.  NINDS funding strategy may be 
found at: http://www.ninds.nih.gov/funding/ninds_funding_strategy.htm

INQUIRIES

Inquiries concerning this PA 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.
Neurogenetics and Neurodevelopment
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 2132
Bethesda, MD  20892
Telephone:  (301) 496-5745
FAX:  (301) 402-1501
Email:  gs41b@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

AUTHORITY AND REGULATIONS

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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