NIH GUIDE, Volume 22, Number 21, June 11, 1993

PA NUMBER:  PA-93-094

P.T. 34


  Musculoskeletal System 


  Physiology, Human 


National Institute of Arthritis and Musculoskeletal and Skin Diseases


The National Institute of Arthritis and Musculoskeletal and Skin

Diseases (NIAMS), in collaboration with the Life Sciences Division of

the National Aeronautics and Space Administration (NASA), invites

grant applications on basic, applied, and clinical research projects

focusing on the effects of microgravity on the musculoskeletal



The Public Health Service (PHS) is committed to achieving the health

promotion and disease prevention objectives of "Healthy People 2000,"

a PHS-led national activity for setting priority areas.  This Program

Announcement (PA), Research on the Effects of Microgravity on the

Musculoskeletal System, is related to the priority area of chronic

disabling conditions.  Potential applicants may obtain a copy of

"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0) or

"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)

through the Superintendent of Documents, Government Printing Office,

Washington, DC 20402-9325 (telephone 202-783-3238).


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.

Foreign institutions are not eligible for the First Independent

Research Support and Transition (FIRST) Award (R29).  Applications

from minority individuals and women are encouraged.


Support will be offered through regular research project grants (R01)

and FIRST Awards (R29).  Because the nature and scope of the research

proposed in response to this PA may vary, it is anticipated that the

size of an award will vary also.


Space travel encompasses many technological challenges and

opportunities.  As the U.S. Space Program prepares for extended

duration space flights on the Space Shuttle, Space Station Freedom,

and on exploration missions to the Moon and Mars, it is important

that life sciences research provide a thorough understanding of the

many physiologic changes that occur in a microgravity environment.

Prolonged exposure to weightlessness diminishes functional capacity,

performance and endurance of the musculoskeletal system, even at

submaximal loads, and thus elicits concern about the health and

well-being of space travellers, especially as space flight is

extended in time.  This research should also lead to development of

effective countermeasures to any effects that may be detrimental to

the functional capacity, health, or well-being of crew members.

The musculoskeletal system has the capacity to adapt its structural

and functional properties in accordance with the type and degree of

stimuli imposed on it.  Prolonged space travel is essentially a

period of significant unloading of the musculoskeletal system.

Exposure to weightlessness results in structural and functional

adaptations that place the musculoskeletal system on the low end of

the continuum ranging from complete disuse to maximal load-bearing.

Evidence from previous space flights and ground-based research

indicates that the musculoskeletal system is functionally impaired

with increasing duration of weightlessness.

Space flight has been consistently accompanied by loss of bone and

negative calcium balance.  Bone density may decrease by as much as 10

percent per year. This change in bone density is preceded by

significant and more rapid weakening and atrophy of skeletal muscle.

A workshop on the "Effects of Space Travel on the Musculoskeletal

System" was co-sponsored by the NIAMS and NASA in October 1990.  The

workshop provided state-of-the-art knowledge, identified research

gaps and windows of opportunity, and recommended future directions

for research on understanding the musculoskeletal system's adaptation

to exposure to weightlessness, including development of adequate

physiologic and performance-based countermeasures.  Although there is

a research base of some knowledge on the complex bone remodelling

process and potential biological agents and factors that may be able

to restore or prevent bone loss on earth, more research is required

in space applications of these technologies. Considerably less

information is available on understanding how force development by

skeletal muscle is essential in maintaining bone integrity.

Likewise, there is a strong science base regarding muscle physiology,

but knowledge in microgravity environments is limited.  A workshop

summary, The Effects of Space Travel on the Musculoskeletal System,

has been published (NIH Publication No. 93-3482, November 1992) and

is available upon request from the Program Officials listed under


The NIAMS, in collaboration with NASA, is interested in soliciting

grant applications whose research focus is on the effects of

microgravity on the musculoskeletal system.

The major objective of this Program Announcement is to stimulate

basic, applied, and clinical research on elucidating the effects of

microgravity on the musculoskeletal system.  Development of

mechanism-related hypotheses encompassing both basic and applied

science is desirable.  While the research focus is on reduced gravity

conditions, well justified studies on musculoskeletal responses to

increased gravity conditions may be instrumental in understanding the

pathogenesis of bone and skeletal muscle weakness and loss during

exposure to microgravity environments.  A key feature of the basic

research component is understanding the cellular mechanisms whereby

alterations in the musculoskeletal system are evoked in response to

external loading and loading histories.  For example, how does

loading or lack of it affect cellular processes and regulatory

factors that control turnover of matrix and contractile proteins?

Basic research would focus on the physiologic changes of bone and

skeletal muscle in cell and tissue cultures that occur in a low or

high gravity environment.

Applicants are also encouraged for appropriate applied/clinical

studies addressing microgravity-induced osteopenia and skeletal

muscle atrophy in whole animal and human experiments.  Utilization of

available technologies including, but not limited to, the following

are encouraged: simulations of weightlessness (e.g., suspension limb

model), centrifugation (alterations in 'g' forces), and bedrest.

Applicants may collaborate with NASA scientists (based on

availability of resources), especially in gaining access to hospital

beds in a clinical setting and low or high gravity environment


Special emphasis should be placed on elucidating the etiology of the

pathogenesis of bone loss and skeletal muscle weakness during

exposure to an altered gravity environment and on research activities

that will address the important issues of prevention and treatment of

bone and skeletal muscle loss from microgravity exposure.

The research identified in this announcement is specifically targeted

to the response of bone and muscle to alterations in environmental

gravity that lead towards understanding the effects of space travel.

Examples of research activities identified by the Workshop include,

but are not limited to:

o  Quantification of rate, magnitude, and cellular origins of bone

and skeletal muscle cell loss in conditions of altered gravity;

o  Influence of skeletal muscle second messengers on bone growth

under microgravity environments;

o  Hormonal and growth factor effects on bone and muscle cell

function and metabolism in relation to gravity effects;

o  Characterization of bone loading in bedrest subjects;

o  Bone and muscle cell responses to altered mechanical stress and


o  Evaluation of 3-D structure and integrity of the musculoskeletal

system and constituent tissues in response to changes in gravity;

o  Bone and muscle cell expression, including characterization of

cellular receptors, signal transduction and messengers in response to

gravity changes;

o  Alterations in blood flow and its impact on cellular metabolism in

microgravity; and

o  Development of therapeutic agents that restore bone loss and

muscle weakness due to space travel.

These areas of research are neither prioritized nor meant to be

restrictive. Investigators are encouraged to submit applications in

any meritorious area of research responsive to the general research

objectives of this Program Announcement.





NIH policy is that applicants for NIH 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 form PHS 398 (rev.

9/91) in Sections 1-4 of the Research Plan AND summarized in Section

5, Human Subjects.  Applicants 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, and Hispanics).  The

rationale for studies on single minority population groups must be


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 trials.

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



Applications are to be submitted on grant application form PHS 398

(rev. 9/91).  Applications will be accepted at the standard

application deadlines indicated in the application kits.

Application kits are available at most institutional offices of

sponsored research and may also be obtained from the Office of Grants

Inquiries, Division of Research Grants, National Institutes of

Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone

301/710-0267.  The title and number of the announcement must be typed

in Section 2a on the face page of form PHS 398.

The completed original application and five legible copies of Form

PHS 398 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 PHS

referral guidelines.  Applications will be reviewed for scientific

and technical merit by initial review groups of the Division of

Research Grants.  Following scientific-technical review, applications

will receive a second-level review by the National Arthritis and

Musculoskeletal and Skin Diseases Advisory Council or by other

relevant advisory boards and/or councils.


Applications will compete for available funds with all other approved

applications.  The following criteria will be considered in the

making of funding decisions:

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

o  Availability of funds; and

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.

Inquiries regarding programmatic issues may be directed to:

Stephen L. Gordon, Ph.D.

Musculoskeletal Diseases Branch

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Westwood Building, Room 407

Bethesda, MD  20892

Telephone:  (301) 594-9951

Richard W. Lymn, Ph.D.

Muscle Biology Branch

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Westwood Building, Room 403

Bethesda, MD  20892

Telephone:  (301) 594-9959

Victor S. Schneider, M.D.

Life Sciences Division

National Aeronautics and Space Administration

Code SBM

300 E Street, SW

Washington, DC  20546

Telephone:  (202) 358-2359

Direct inquiries regarding fiscal matters to:

Ms. Diane M. Watson

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Westwood Building, Room 732A

Bethesda, MD  20892

Telephone:  (301) 594-9965


This program is described in the Catalog of Federal Domestic

Assistance No. 93.846, Arthritis, Musculoskeletal and Skin Diseases

Research.  Awards will be made under the authority of the Public

Health Service Act, Title III, Section 301 (Public Law 410, 78th

Congress, as amended, 42 USC 241) and administered under PHS grants

policies and Federal regulations 42 CFR Part 52 and 45 CFR Part 74.

This program is not subject to the intergovernmental review

requirements of Executive Order 12372 or Health Systems Agency



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