PRECURSOR CELLS IN SKELETAL MUSCLE REPAIR AND HYPERTROPHY

RELEASE DATE:  July 25, 2002

PA NUMBER:  PA-02-136

EXPIRATION DATE:  March 30, 2006

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) 
 (http://www.niams.nih.gov/)

National Institute on Aging (NIA) 
 (http://www.nia.nih.gov)

National Institute of Child Health and Human Development (NICHD) 
 (http://www.nichd.nih.gov/)

National Institute of Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov)

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE

The National Institute of Arthritis and Musculoskeletal and Skin 
Diseases (NIAMS), the National Institute on Aging (NIA), the National 
Institute of Child Health and Human Development (NICHD) and the 
National Institute of Neurological Disorders and Stroke (NINDS) 
encourage investigator-initiated research grant applications to 
isolate, characterize and identify precursor cells required for normal 
growth and repair of injured, aged, or diseased muscle.  Goals include 
determining factors responsible for migration, proliferation, and 
differentiation of precursor cells following muscle injury or increased 
exercise.  This includes characterizing molecular controls responsible 
for the quiescence of muscle satellite cells and determining metabolic 
and motile properties of satellite cells while they are quiescent.  
Researchers are encouraged to develop strategies using muscle satellite 
and stem cells in therapies for human disease and enhanced repair of 
muscle injury and as cellular vectors of genes.			

RESEARCH OBJECTIVES 

Background

Mammalian muscle contains a set of cells capable of regeneration and 
repair.  These regenerative cells play an important role in the 
considerable growth of post natal muscle, with skeletal muscle 
representing 40-50 % of the weight of adults.  An important question in 
muscle development and muscle repair is the origin of these cells and 
their relationship to stem cells that circulate within the blood.

Normal repair and exercise induced cellular hypertrophy of skeletal 
muscle is mediated by quiescent, undifferentiated cells.  These are 
called satellite cells because of their anatomic location, within the 
basal lamina at the periphery of mature skeletal muscle fibers.  
Following muscle injuries, or in response to increasing work demands, 
satellite cells are mobilized to proliferate, differentiate, and fuse 
into multinucleate myofibers.  Little is known about the developmental 
origins of satellite cells or the mechanisms that restrict 
differentiation and maintain their quiescence while associated within 
functioning muscles.  Similarly, there is little characterization of 
the molecular steps which occur in the recruitment of satellite cells 
for repair from injury or disease.  In addition, little is understood 
about possible changes in potential for differentiation or population 
dynamics of satellite cells with aging that may be important to loss of 
muscle mass in the elderly.

Recent research showed the existence of  a small population of muscle-
derived stem cells that are multipotent, which can contribute to the 
formation of blood and bone tissue as well as muscle.  Additionally, 
muscle that is repairing itself can recruit circulating non-muscle stem 
cells and convert them into myogenic precursors.  Knowledge of how such 
cells function in muscle growth is limited.

Scope and Objectives

This initiative encourages research on cells involved in skeletal 
muscle growth and repair.  Goals include determining factors 
responsible for migration, proliferation, and differentiation of 
precursor cells following muscle injury or increased exercise.  This 
includes characterizing molecular controls responsible for the 
quiescence of muscle satellite cells and determining metabolic and 
motile properties of satellite cells while they are quiescent.  

Researchers are encouraged to develop strategies using muscle satellite 
and stem cells in therapies for human disease and enhanced repair of 
muscle injury and as cellular vectors of genes.  One such aim is to 
develop methods that enhance repair of muscle injuries with minimal 
fibrosis and scarring.

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 understanding precursor cells involved in skeletal muscle 
growth and repair.  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.

o  Projects to identify, isolate, culture and characterize cells that 
are precursors of muscle growth or regeneration. 

o  Projects to generate and use panels of markers for use in 
characterization and isolation of skeletal muscle precursor cells.

o  Studies to determine the origins and fates of muscle precursor 
cells.

o  Characterization of differences between skeletal muscle cells and 
other muscle precursor cells derived from muscle.

o  Research on mechanisms governing the role of muscle precursor cells 
in muscle plasticity and adaptation and aging.

o  Research to characterize molecular controls responsible for the 
quiescence of muscle satellite cells and determining metabolic and 
motile properties of satellite cells while they are quiescent, 
including quiescent satellite cells in aged muscle.  

o Characterization of  biological functions of muscle precursor cells.

o Research to develop and optimize methodologies for expanding the 
differentiation of muscle precursor cell populations, or understanding 
if precursor populations from aged muscle have altered requirements for 
differentiation.

o  Projects to create methods of culture to maintain muscle precursor 
cells in stages when they proliferate.

o Studies to elucidate mechanisms of muscle precursor cell 
differentiation

o Research to develop and optimize methodologies for directing the 
differentiation of muscle precursor cell populations.

o Research to minimize inappropriate differentiation during the repair 
process that leads to fibrosis (contractures) or calcification 
(myositis ossificans, fibrodysplasia ossificans progressiva.)

o Applying muscle precursor cell therapies to muscle diseases and 
disuse muscle atrophy or wasting (also called sarcopenia).

o Research to develop strategies using muscle satellite and stem cells 
in therapies for human disease and enhanced repair of muscle injury and 
as cellular vectors of genes.

o  Use of precursor cells in the context of exercise, functional 
electrical stimulation (FES) or other therapeutic strategies.

MECHANISM OF SUPPORT

This PA will use the NIH individual research project grant (R01) award 
mechanism.  As an applicant, you will be solely responsible for 
planning, directing, and executing the proposed project.

This PA uses just-in-time concepts.  It also uses the modular as well 
as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.  Otherwise 
follow the instructions for non-modular research grant applications.

Investigators should contact program staff listed under INQUIRIES to 
discuss applications using other mechanisms, such as the program 
project grant.

ELIGIBLE INSTITUTIONS 

You may submit an application if your institution has any of the 
following characteristics:
	
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA and welcome the 
opportunity to answer questions from potential applicants.  Inquiries 
may fall into two areas:  scientific/research and financial or grants 
management issues:

Direct your questions about scientific/research issues to: 

Richard W. Lymn, Ph.D.
Muscle Biology Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
One Democracy Plaza
6701 Democracy Blvd., Suite 800
Bethesda, MD  20892-4872
Telephone:  (301) 594-5128
FAX:  (301) 480-4543
Email: LymnR@mail.nih.gov 

Jill L. Carrington, Ph.D.
Musculoskeletal Biology 
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue Suite 2C231
Bethesda, MD   20892
Telephone: (301) 496-6402
FAX: (301) 402-0010
Email: carringtonj@nia.nih.gov

Ralph M. Nitkin, Ph.D.
National Center for Medical Rehabilitation Research
National Institute of Child Health and Human Development
Building 6100E/Room 2A03
6100 Executive Blvd MSC 7510
Bethesda, MD 20892-7510
Email: rn21e@nih.gov

Daofen Chen, Ph.D.NINDS/NIH
Neuroscience Center, Room 2131 
6001 Executive Boulevard 
Bethesda, MD 20892-9523 
Rockville, MD 20852 (courier service only) 
Telephone:  (301) 496-1917
FAX:  (301) 402-1501 
Email:  daofen.chen@nih.gov   

o Direct your questions about financial or grants management matters 
to:

Melinda Nelson
Grants Management Officer
National Institute of Arthritis and Musculoskeletal and Skin Diseases
One Democracy Plaza
6701 Democracy Blvd. Suite 800
Bethesda, MD  20892-4872
Telephone:  (301) 594-3535
FAX:  (301) 480-5450
Email:  nelsonm@mail.nih.gov

Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD   20892-9205
Telephone: (301) 496-1472
FAX: (301) 402-3672
Email: whippl@nih.gov

Christopher Myers
Grants Management
National Institute of Child Health and Human Development
Building 6100E/Room 8A17
6100 Executive Blvd MSC 7510
Bethesda, MD 20892-7510
Email: cm143g@nih.gov

Karen Dunlap
Grants Management Officer
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd.  Rm. 3250
Rockville, MD 20892
Telephone: (301) 496-9231
FAX: (301) 402-0219
Email: dunlapk@ninds.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

APPLICATION RECEIPT DATES: Applications submitted in response to this 
program announcement will be accepted at the standard application 
deadlines, which are available at 
http://grants.nih.gov/grants/dates.htm.  Application deadlines are also 
indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications 
requesting up to $250,000 per year in direct costs must be submitted in 
a modular grant format.  The modular grant format simplifies the 
preparation of the budget in these applications by limiting the level 
of budgetary detail.  Applicants request direct costs in $25,000 
modules.  Section C of the research grant application instructions for 
the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER 
YEAR: Applications requesting $500,000 or more in direct costs for any 
year must include a cover letter identifying the NIH staff member 
within one of NIH institutes or centers who has agreed to accept 
assignment of the application.   

Applicants requesting more than $500,000 must carry out the following 
steps:
	
1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
  
3) Identify, in a cover letter sent with the application, the staff 
member and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended 
or revised version of these grant application types. Additional 
information on this policy is available in the NIH Guide for Grants and 
Contracts, October 19, 2001 at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the checklist, and 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)

APPLICATION PROCESSING: Applications must be received by or mailed on 
or before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR 
will not accept any application in response to this PA that is 
essentially the same as one currently pending initial review unless the 
applicant withdraws the pending application.  The CSR will not accept 
any application that is essentially the same as one already reviewed.  
This does not preclude the submission of a substantial revision of an 
application already reviewed, but such application must include an 
Introduction addressing the previous critique.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review 
group convened in accordance with the standard NIH peer review 
procedures (http://www.csr.nih.gov/refrev.htm) will evaluate 
applications for scientific and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed 
to have the highest scientific merit, generally the top half of 
applications under review, will be discussed and assigned a priority 
score
o Receive a second level review by the appropriate national advisory 
council or board
	
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 comments, reviewers will be asked to discuss the 
following aspects of your application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these 
criteria in assigning your application's overall score, weighting them 
as appropriate for each application.  Your 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, 
you may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

(1) SIGNIFICANCE:  Does your study address an important problem? If the 
aims of your application are achieved, how do they advance scientific 
knowledge?  What will be the effect of these studies on the concepts or 
methods that drive this field?

(2) APPROACH:  Are the conceptual framework, design, methods, and 
analyses adequately developed, well integrated, and appropriate to the 
aims of the project?  Do you acknowledge potential problem areas and 
consider alternative tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project 
challenge existing paradigms or develop new methodologies or 
technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to your 
experience level as the principal investigator and to that of other 
researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

PROTECTIONS:  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.

INCLUSION:  The adequacy of plans to include subjects from both 
genders, all racial and ethnic groups (and subgroups), and children as 
appropriate for the scientific goals of the research.  Plans for the 
recruitment and retention of subjects will also be evaluated. (See 
Inclusion Criteria included in the section on Federal Citations, below)

DATA SHARING:  The adequacy of the proposed plan to share data. 

BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

AWARD CRITERIA

Applications submitted in response to a PA will compete for available 
funds with all other recommended applications.  The following will be 
considered in making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities

REQUIRED FEDERAL CITATIONS 

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research 
components involving Phase I and II clinical trials must include 
provisions for assessment of patient eligibility and status, rigorous 
data management, quality assurance, and auditing procedures.  In 
addition, it is NIH policy that all clinical trials require data and 
safety monitoring, with the method and degree of monitoring being 
commensurate with the risks (NIH Policy for Data Safety and Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH:  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 clinical research 
projects unless a clear and compelling justification is provided 
indicating 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 clinical research should read the AMENDMENT 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a 
complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.  
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) all 
applications or proposals and/or protocols must 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) 
investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS: The NIH maintains a policy 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 is available at  
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  
NIH policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  You will find this policy 
announcement in the NIH Guide for Grants and Contracts Announcement, 
dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.


PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

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.   Furthermore, we caution reviewers that their 
anonymity may be compromised when they directly access an Internet 
site.

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. 
Potential applicants may obtain a copy of "Healthy People 2010" at  
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance Nos. 93.846,  93.866,  93.929 and 93.853 
and is not subject to the intergovernmental review requirements of 
Executive Order 12372 or Health Systems Agency review.  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 described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the 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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