PATHOGENESIS AND THERAPY OF THE MUSCULAR DYSTROPHIES

Release Date:  March 20, 1998

PA NUMBER:  PA-98-044

P.T.

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

PURPOSE

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

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention goals of "Healthy People 2000," a PHS-led national
activity for setting priorities.  This program announcement, Pathogenesis and
Therapy of the Muscular Dystrophies, is related to the priority area chronic
disabling conditions.  Potential applicants may obtain a copy of "Healthy People
2000" (Full Report: No. 017-001-00474-0 or Summary Report:  Stock No. 017-001-
00473-1) through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-512-1800).

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 support mechanisms for grants in this area will be the investigator-initiated
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.  Applicants for program projects are
requested to contact the NINDS or NIAMS representative listed under INQUIRIES as
early as possible in the planning stages.  Applicants must receive permission
from the NINDS or NIAMS prior to the submission of an application requesting more
than $500,000 in direct costs per year for any year of the proposed study.

RESEARCH OBJECTIVES

Background

The muscular dystrophies are a heterogeneous group of inherited neuromuscular
diseases characterized by weakness and wasting of muscles.  Precise incidence and
prevalence figures are difficult to determine, and most individual forms of
muscular dystrophy are rare.  The total impact, however, is high, as tens of
thousands of people are affected with some type of muscular dystrophy in the
United States alone.  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.

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 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 childhood or teen-age onset.  The dominant LGMDs usually show 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).

Myotonic dystrophy is the most common form of muscular dystrophy in adults.  It
is dominantly inherited and affects brain, lens, and heart in addition to
skeletal muscles.  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.

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 and skeletal muscle 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 onset.  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.

Duchenne muscular dystrophy (DMD) is the most common form, affecting
approximately one in 3,500 male births.  The sex-linked disease is characterized
by muscle necrosis and regeneration.  Eventually, the regeneration cannot keep
up with the necrosis, resulting in progressive muscle fiber loss.  Affected boys
are usually wheelchair-bound 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.  Recent animal model studies have suggested that utrophin, a
structurally similar protein present at the neuromuscular junction, may somehow
be made to compensate for dystrophin.

A milder variant, Becker muscular dystrophy (BMD), is caused by a different
defect in the DMD gene, usually an internal in-frame deletion that produces
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 people 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.

Scope and Objectives

Investigators with diverse scientific interests are invited to apply their
expertise to basic and applied research to enhance our understanding of the
pathogenesis of the muscular dystrophies, including the development of
appropriate animal models.  Examples that illustrate possible areas of research
to be considered are presented below.  They are intended only to provide a broad
direction for research into several of the muscular dystrophies and should be
considered illustrative and not restrictive.  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  further pursue the development of appropriate animal models

o  develop improved diagnostic procedures

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

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

o  attempt to improve protein expression from transplanted myoblasts to a useful
level

o  continue to explore the development of new types of therapy, including gene
therapy

Some possible areas of research that are specific to one form of muscular
dystrophy include:

o  facioscapulohumeral muscular dystrophy.  continue the sequencing of the entire
4q35 region; investigate the position effect hypothesis and its basis in
chromatin structure.

o  limb-girdle and severe childhood autosomal recessive muscular dystrophy: 
examine pathogenic mechanisms in cases not caused by sarcoglycan defects; study
the role of dystrobrevin deficiency in the pathogenesis

o  myotonic dystrophy:  study the pathogenic mechanisms involved in the CGT
triplet repeat; identify factors other than length of triplet repeat that are
related to phenotypic expression

o  Emery-Dreifuss muscular dystrophy:  determine the function of emerin in
skeletal and cardiac muscle; determine the extent to which other genes can cause
EMD-like symptoms

o  congenital muscular dystrophy:  investigate the role of merosin with other
proteins in peripheral myelinogenesis; determine how different molecular defects
in merosin lead to variable phenotypes

o  Duchenne and Becker muscular dystrophy:  study the development and function
of the dystrophin-glycoprotein complex; investigate the compensatory effects
observed with the overexpression of utrophin

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 is 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
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513), and in the NIH GUIDE FOR GRANTS AND CONTRACTS, Volume 23,
Number 11, March 18, 1994.

Investigators may also obtain copies from these sources or from the program staff
or contact person listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
5/95) and will be accepted at the standard application deadlines as indicated in
the application kit.  These forms are available at most institutional offices of
sponsored research and may be obtained 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: 
[email protected].

Check "YES" in item 2a on the face sheet of the application and type 
"Pathogenesis and Therapy of the Muscular Dystrophies."

Applicants for the P01 should contact the NINDS and NIAMS program officers listed
under INQUIRIES to discuss their planned projects and to request the Institute's
guidelines for program project applications.

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
Dr. Nichols or Dr. Lymn at the addresses listed under INQUIRIES to expedite
processing and review of applications for multidisciplinary efforts.

REVIEW CONSIDERATIONS

Applications that are complete will be evaluated for scientific and technical
merit by an appropriate 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.

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?

o  Appropriateness of the proposed budget and duration in relation to the
proposed research.

o  Adequacy of plans to include both genders and minorities and their subgroups
as appropriate for the scientific goals of the research.  Plans for the
recruitment and retention of subjects will be evaluated.

o  The initial review group will also examine the provisions for the protection
of human and animal subjects, and the safety of the research environment.

o  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 and research center 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 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

INQUIRIES

Written, telephone, and e-mail inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Paul L. Nichols, Ph.D.
Division of Convulsive, Infectious, and Immune Disorders
National Institute of Neurological Disorders and Stroke
Federal Building, Room 504
Bethesda, MD  20892-9160
Telephone:  (301) 496-1431
FAX:  (301) 402-2060
Email:  [email protected]v

Richard W. Lymn, Ph.D.
Muscle Biology Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building Room 5AS49E
Bethesda, MD  20892-6500
Telephone:  (301) 594-5128
FAX:  (301) 480-4543
Email:  [email protected]

Direct inquiries regarding fiscal matter to:

Ms. Dawn Richardson
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Federal Building, Room 1004
Bethesda, MD  20892
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  [email protected]

Ms. Sally A. Nichols
Grants Management Officer
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS 49F
Bethesda, MD  20892-6500
Telephone:  (301) 594-3535
FAX:  (301) 480-5450
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.853 , 93.854, and 93.846.  Awards are made under authorization of the Public
Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law
99-150, 42 USC 241 and 285) and administered under PHS grant policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74. 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 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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