NIH GUIDE, Volume 21, Number 12, March 27, 1992

PA NUMBER:  PA-92-64

P.T. 34


  Musculoskeletal System 


  Disease Model 

  Clinical Medicine, General 

National Institute of Arthritis and Musculoskeletal and Skin Diseases

National Institute of Child Health and Human Development


The National Institute of Arthritis and Musculoskeletal and Skin

Diseases (NIAMS) and National Institute of Child Health and Human

Development (NICHD) invite grant applications for basic and clinical

research projects on heritable disorders of connective tissue.


Applications may be submitted by domestic and foreign, non-profit and

for-profit, public and private organizations, such as universities,

colleges, hospitals, laboratories, units of State and local

governments, and eligible agencies of the Federal government.  However,

foreign institutions are not eligible for the First Independent

Research Support and Transition (FIRST) Award (R29) and the career

development awards (K04, K08, K11).  Applications from minority

individuals and women are encouraged.


Support will be offered through research projects grants (R01), FIRST

awards (R29), fellowship training (F32, F33, T32), and career

development awards (K04, K08, K11).


Over 200 distinct disorders are recognized as being caused by mutations

in genes that encode matrix proteins or in genes that ultimately affect

the structure of the extracellular matrix.  Collectively, these

disorders are termed heritable disorders of connective tissue.  There

is a wide range of anatomic sites and clinical manifestations that can

result from these conditions.  In total, it is estimated that heritable

disorders of connective tissue account for major and, in some cases,

life-threatening illnesses in approximately half a million people in

the United States.

Some mutations in genes may give rise to severe abnormalities, while

others may produce milder symptoms.  There is also recent scientific

evidence that mild phenotypes may appear in more common disorders, such

as osteoarthritis and osteoporosis.

On April 9-11, 1990, the NIAMS, the NICHD, and the Coalition for

Heritable Disorders of Connective Tissue sponsored a Workshop on

Heritable Disorders of Connective Tissue at the National Institutes of

Health.  The focus of the Workshop was to review the current status of

research in this field and to identify important directions for future

research.  Major advances have been achieved in identifying molecular

components of the extracellular matrix, in isolating and characterizing

the genes that encode these proteins, in defining biosynthetic pathways

and interactions between proteins, and in characterizing specific

mutations in some disease categories.

The Workshop participants described the need for continued integration

of insights gained from collaborative research perspectives, such as

molecular biology, biochemistry, physical biochemistry, anatomy, and

clinical genetics, the need to identify cohorts of patients and

families with rare disorders, and the need to recognize

structure-function relationships in interpreting genetic mutations.

Some broad areas of recommended research directions include, but are

not limited to:

o  Identification and characterization of mutations in many disease


o  Structure-function relationships of normal matrix molecules;

o  Developmental regulation of matrix formation;

o  Multi-disciplinary analysis of disease mechanisms;

o  Clinical studies:  natural history and clinical trials in these


o  Identification and study of animal models using transgenic


o  Application of genetic linkage strategies to these inherited


o  Pursuit of the molecular/genetic basis of selected common diseases.

The above examples of research areas related to heritable disorders of

connective tissue are not presented in a priority order and are not

intended to restrict the wide range of meritorious areas in which

investigators may apply.  A complete report of the 1990 Workshop is

available upon request from Dr. Stephen L. Gordon at the address below.





NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical

research grants and cooperative agreements are required to include

minorities and women in study populations so that research findings can

be of benefit to all persons at risk of the disease, disorder or

condition under study; special emphasis must be placed on the need for

inclusion of minorities and women in studies of diseases, disorders and

conditions which disproportionately affect them.  This policy is

intended to apply to males and females of all ages.  If women or

minorities are excluded or inadequately represented in clinical

research, particularly in proposed population-based studies, a clear

compelling rationale must be provided.

The composition of the proposed study population must be described in

terms of gender and racial/ethnic group.  In addition, gender and

racial/ethnic issues should be addressed in developing a research

design and sample size appropriate for the scientific objectives of the

study.  This information must be included in the form PHS 398 in

Section 2, 1-4 of the Research Plan and summarized in item 5, Human

Subjects.  Applicants/offerors are urged to assess carefully the

feasibility of including the broadest possible representation of

minority groups.  However, NIH recognizes that it may not be feasible

or appropriate in all research projects to include representation of

the full array of United States racial/ethnic minority populations

(i.e., Native Americans (including American Indians or Alaskan

Natives), Asian/Pacific Islanders, Blacks, Hispanics).  The rationale

for studies on single minority population groups must be provided.

For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology, prevention

(and preventive strategies), diagnosis, or treatment of diseases,

disorders or conditions, including, but not limited to, clinical


The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded.  However,

every effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including


If the required information is not contained within the application,

the review will be deferred until the information is provided.

Peer reviewers will address specifically whether the research plan in

the application conforms to these policies.  If the representation of

women or minorities in a study design is inadequate to answer the

scientific question(s) addressed and the justification for the selected

study population is inadequate, it will be considered a scientific

weakness or deficiency in the study design and will be reflected in

assigning the priority score to the application.

All applications for clinical research submitted to NIH are required to

address these policies.  NIH funding components will not award grants

or cooperative agreements that do not comply with these policies.


Applications are to be submitted on the grant application form PHS 416-

1 (rev. 4/89) for individual fellowships, for other awards use PHS 398

(rev. 9/91) and will be accepted at the standard application deadlines

indicated in the application kit.

Application kits are available at most institutional business offices

and may be obtained from the Office of Grants Inquiries, Division of

Research Grants, National Institutes of Health, Westwood Building, Room

449, Bethesda, MD 20892, telephone 301/496-7441.  The title and number

of the announcement must be typed in Section 2a on the face page of the

PHS 398.

The completed original application and five legible copies of the PHS

398 or two copies of the PHS 416-1 must be sent or delivered to:

Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**


Applications will be assigned on the basis of established Public Health

Service referral guidelines.  Applications will be reviewed for

scientific and technical merit by initial review groups of the Division

of Research Grants, NIH, or by the review group of the relevant

Institute, Center, or Division (ICD), in accordance with the standard

NIH peer review procedures.  Following scientific-technical review, the

applications will receive a second-level review by the appropriate

national advisory council.


Applications will compete for available funds with all other approved

applications assigned to that ICD.  The following criteria will be

considered in making funding decisions:

o  Quality of the proposed project as determined by peer review;

o  Availability of funds;

o  Program balance among research areas of the announcement.


Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.

Direct inquiries for the NIAMS regarding programmatic issues to:

Stephen L. Gordon, Ph.D.

Chief, Musculoskeletal Diseases Branch

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Westwood Building, Room 407

Bethesda, MD  20892

Telephone:  (301) 496-7495

Direct inquiries for the NICHD regarding programmatic issues to:

Delbert Dayton, M.D.

Chief, Genetics & Teratology Branch

National Institute of Child Health and Human Development

Executive Plaza North, Room 643

Rockville, MD  20892

Telephone:  (301) 496-5541

Direct inquiries for the NIAMS regarding fiscal matters to:

Ms. G. Carol Clearfield

National Institute of Arthritis and Musculoskeletal and Skin Diseases

5333 Westbard Avenue, Room 726B

Bethesda, MD  20892

Telephone:  (301) 496-6529

Direct inquiries for the NICHD regarding fiscal matters to:

Douglas Shawver

National Institute of Child Health and Human Development

Executive Plaza North, Room 505

Rockville, MD  20892

Telephone:  (301) 496-1303


This program is described in the Catalog of Federal Domestic Assistance

No. 93.846, Arthritis, Musculoskeletal and Skin Disease Research,

93.862, Genetics Research, 93.865, Research for Mothers and Children.

Awards are made under authorization of the Public Health Service Act,

Title IV, Part A (Public Law 78- 410, as amended by Public Law 99-158,

42 USC 241 and 285) and administered under PHS grants 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.


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