PROGRAM ANNOUNCEMENT TITLE:  ROLE OF MUSCULOSKELETAL MICROVASCULATURE 
IN FITNESS AND DISEASE

PA NUMBER:  PA-02-104

RELEASE DATE:  May 2, 2002

EXPIRATION DATE:  July 30, 2005

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
 (http://www.niams.nih.gov/)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov/)

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanisms 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) and the National Institute of Diabetes and Digestive 
and Kidney Diseases (NIDDK) encourage investigator-initiated research 
grant applications on the role of musculoskeletal microvasculature in 
fitness and disease.  An important area is to characterize changes in 
skeletal muscle perfusion as a result of disease, injury, or exercise 
training. Responses to this program announcement may include studies in 
appropriate animal models or preclinical or clinical studies.

RESEARCH OBJECTIVES 

Background

Skeletal muscles require strikingly different levels of nutrients and 
oxygen depending on their level of activity.  Research shows that 
muscle self-adapts in many ways,  responding to changes in activity 
patterns.  This includes changes in the protein mass and composition of 
muscle.  There is also significant change in skeletal muscle 
vasculature, including an increase in capillary density.  The change in 
muscle vasculature allows an increased flow of blood and nutrients into 
muscles during exertion, supporting an increased level of force and 
delaying fatigue.  Decreased activity, resulting from injury or 
disease, results in muscle atrophy and a decrease in the density of 
capillaries.  The level of physical activity also has a role in fluid 
circulation in other musculoskeletal structures, especially poorly 
vascularized regions such as tendons and joints. 

Recent studies found increased amounts of angiogenic factors following 
increased skeletal muscle activity.  Researchers detected increased 
concentrations of vascular endothelial growth factor, fibroblast growth 
factor-2, and transforming growth factor-beta-1. While the regulating 
mechanisms in this response are not clear, present data indicate 
reduced oxygen tension, increased average calcium concentrations, and 
other metabolic alterations in the skeletal muscle as possible stimuli.  
Different exercise-associated stimuli may all contribute to exercise-
induced angiogenesis in skeletal muscle, possibly through differing 
factors and mechanisms. Understanding these processes is important for 
the elucidation of mechanisms mediating exercise responsiveness in 
skeletal muscle, but also for the potential that such understanding 
might bring to the treatment and prevention of human diseases.

Alterations in capillary basal lamina of skeletal muscle are seen in 
polymyositis, periodic paralysis, and Duchenne muscular dystrophy 
(DMD). Depending on the disease, there may be endothelial thickening or 
decrease in the density of capillaries.  Recent work suggests that 
severity of skeletal muscle disease may be related to changes in muscle 
microcirculation. In one mouse model for DMD, the muscles show 
decreased levels of nitric oxide synthase, which has a role in 
regulating blood flow.  Earlier research indicated that the highly 
restricted microvasculature in skeletal muscles of this mouse has a 
very negative effect on general health, producing cardiomyopathy and 
premature death in the mouse model.  This suggests that DMD and other 
skeletal muscle diseases might increase resistance to blood flow, 
resulting in further damage to muscles and generalized symptoms.  
Alterations in muscle microcirculation may also play a role in the 
pathology of obesity and the development of diabetic complications such 
as peripheral neuropathy and the diabetic foot.

Scope and Objectives

This initiative encourages applications that clarify two aspects of 
musculoskeletal microcirculation.  One aim is to understand and 
characterize how injuries, disease and different levels of physical 
activity result in changes in the microcirculation within skeletal 
muscle and other musculoskeletal tissues.  A second aim is to determine 
the role of such changes in maintaining or compromising health.  The 
announcement encourages projects that explore molecular and genomic 
mechanisms involved in cellular changes in musculoskeletal fluid 
circulation in response to disease, overuse injuries, or changing 
patterns of physical activity.  This includes mechanisms responsible 
for the detection and signaling of changes in levels of substances such 
as oxygen and calcium, and the mechanisms that mediate adaptive changes 
in metabolism, oxygen sensing, and gene expression. 

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 changes in musculoskeletal microvasculature that 
occur due to illness, injury, or altered physical activity. 

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  Influence of muscle injury or disease on the plasticity of the 
skeletal muscle vascular system. 

o  Studies on dynamic interrelationships between patterns of skeletal 
muscle activity and its vasculature and perfusion.
  
o Studies to improve understanding of changes in circulation within the 
musculoskeletal system in response to patterns of use. This includes 
studies on the mechanisms involved in altered micro-vasculature and 
extra-vascular circulation in muscle, bone, and joints. Investigators 
should explore differences due to endurance and resistance training.

o  Development and validation of appropriate animal models to examine 
changes in skeletal muscle microvasculature due to disease and patterns 
of physical activity. 

o  Characterization in muscle of the functional and metabolic 
consequences of exercise and disease-related changes in skeletal muscle 
microvasculature.

o  Improved quantitative measures of vascular changes in skeletal 
muscle and blood flow heterogeneity, including dynamic measures.
		
o  Using improved imaging techniques to better characterize and 
understand changes in musculoskeletal fluid circulation due to injury, 
disease or physical activity.

o  Exploring relationships between inflammatory cells, muscle cell 
death, and blood vessels. 

o Characterize the role of healthy and diseased skeletal muscle in 
defining total peripheral resistance.

o Elucidation of the signal transduction, gene regulating, and 
mitochondrial mechanisms that mediate oxygen sensing in skeletal 
muscle, and of the time course and oxygen level threshold for adaptive 
changes in cellular, local, or systemic responses.

o Identification and characterization of cellular mechanisms that may 
regulate vascular tone in response to intermittent hypoxia such as the 
nitric oxide synthase system and the microsomal electron transporting 
systems associated with P450 enzymes.

o  Influence of altered skeletal muscle blood flow on its metabolism 
and response to circulating factors.

o Studies to understand the effects of obesity, weight loss or gain on 
parameters of skeletal muscle microvasculature, perfusion and 
interaction with muscle metabolism.

o Studies to extend knowledge concerning the pathology, mechanism and 
heterogeneity of microvascular dysfunction in skeletal muscle beds 
secondary to diabetes, and the metabolic consequences of this 
dysfunction.

MECHANISMS OF SUPPORT

This PA will use the NIH individual research project grant (R01) and 
the program project grant (P01) award mechanisms.  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 
https://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 standard instructions for completing the PHS 398 grant 
application form.

Applications for program project grants may only be submitted from 
domestic organizations and investigators are requested to contact the 
NIAMS or NIDDK representative listed under INQUIRIES as early as 
possible in the planning stages.

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 answer questions from potential applicants.  Inquiries may 
fall into three areas:  scientific/research, peer review, and financial 
or grants management issues:

Direct your questions about scientific/research issues to: 
Richard W. Lymn, Ph.D.
Muscle Biology Program
One Democracy Plaza
6701 Democracy Blvd. Suite 801
Bethesda, MD  20892
Telephone:  (301) 594-5128
FAX:  (301) 480-4543
Email: LymnR@mail.nih.gov

Maren R. Laughlin, Ph.D.
Director, Metabolism Program
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 6101, MSC 5460
Bethesda, MD 20892-5460
Telephone (301) 594-8802
FAX: (301) 480-3503
Email: Maren.Laughlin@nih.gov

o Direct your questions about peer review issues to: 

Tommy Broadwater, Ph.D.
Scientific Review Branch, 
National Institute of Arthritis and Musculoskeletal and Skin Diseases
One Democracy Plaza
6701 Democracy Blvd. Suite 801
Bethesda, MD  20892
Telephone: (301) 594-4953
FAX (301) 480-4543 
Email: broadwatert@mail.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 801
Bethesda, MD  20892
Telephone:  (301) 594-3535
FAX:  (301) 480-5450
Email:  nelsonm@mail.nih.gov

Denise Payne
Grants Management Specialist
NIDDK, NIH
2 Democracy Blvd, room 733, MSC 5456
Bethesda, MD  20892
Telephone:  301-594-8845 
Email:  payned@extra.niddk.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 https://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, 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 
https://grants.nih.gov/grants/dates.htm.  Application deadlines are also 
indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: R01 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 
https://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 
https://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 
https://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  
https://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: 
https://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 
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a 
complete copy of the updated Guidelines are available at 
https://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  
https://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 
https://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 
https://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 No. 93.846 and No. 93.847 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 https://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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