AGE-RELATED CHANGES IN TISSUE FUNCTION:  UNDERLYING BIOLOGICAL MECHANISMS (P01)

RELEASE DATE:  September 30, 2002

PA NUMBER:  PA-02-177

EXPIRATION DATE:  September 30, 2003, unless reissued. 

National Institute on Aging (NIA)
 (http://www.nia.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 OF THIS PA  

This program announcement is to solicit multi-component applications on 
biological mechanisms of aging in tissues and organs.  Projects are 
encouraged that significantly advance basic biology research to understand 
how and why changes take place in tissues with age and how those changes 
relate to altered tissue and organ function.  Projects that focus on 
molecular aspects, as well as cellular aspects of tissue aging, are 
encouraged.  Projects are applicable under this announcement that emphasize 
a) molecular and cellular changes that are common among tissues with aging; 
b) that compare mechanisms of aging change in different tissues; and c) that 
investigate the effects of age related changes in one cell type, tissue or 
organ that affect function of another tissue or organ.  Projects must have a 
clear relevance to aging to be considered under this Program Announcement.

On July 12, 2002 NIH issued another program announcement (PA) requesting 
research program grant (R01) applications on age-related changes in tissue 
function.  See http://grants.nih.gov/grants/guide/pa-files/PA-02-128.html 
AGE-RELATED CHANGES IN TISSUE FUNCTION:  UNDERLYING BIOLOGICAL MECHANISMS 
(R01) to view this related PA which requests R01 application mechanisms 
instead of the P01 applications requested in this announcement.

RESEARCH OBJECTIVES

Background

Many tissues, organs and organ systems show decrements in function with age.  
These decrements in function disadvantage the aging population, leading to 
decreases in health and activity and subsequent decreases in the ability of 
individuals to take care of themselves and in overall quality of life.  
Understanding the biological mechanisms of change with age will likely lead 
to treatment or prevention of some resulting disabilities and improved 
quality of life for elderly citizens.

Most organs and tissues of the body exhibit some age-related decline in 
function or increase in disease incidence.  For example, muscle strength 
declines with age.  In addition, bones often weaken, depending both on age 
and changes in hormonal status.  The fragility imposed by weakened muscles 
and bones can result in falls that may be disabling.  The skin undergoes 
visible changes, but also may exhibit impaired wound healing, a threat to 
health.  The growth rate of prostate tissue accelerates in middle-aged men 
leading to the diseases of benign prostatic hyperplasia and possibly prostate 
cancer that are so common in older men.  Female reproductive aging processes 
lead to sharply reduced estrogen levels in middle-aged menopausal women; this 
in turn increases the risk for chronic diseases with increased morbidity and 
mortality.  Serum levels of some hormones (e.g., growth hormone, 
dehydroepiandrosterone, testosterone) decline with age, while other hormones 
(e.g., gonadotropins, insulin) increase with age.  For the most part, the 
functional consequences of these age-related changes in hormone levels are 
not well understood.  It has also been established that overall immune 
function declines with age, leading to an increased susceptibility to various 
infectious diseases.  Age-associated changes are evident in both T and B 
lymphocytes and at higher organizational levels including the thymus, bone 
marrow and germinal centers.  However, the events and mechanisms underlying 
these phenomena are not well understood.  Nervous system function declines 
with age leading to impairments in cognition, motor, sensory and other 
behaviors.  Atrophy of brain tissue and changes in neural circuitry may 
contribute to the functional decline.  Much needs to be learned about the 
cellular and molecular mechanisms responsible for the selective vulnerability 
of brain cells and regions to age-dependent dysfunction and 
neurodegeneration, as occurs in Alzheimer's disease.

Some of the changes seen with aging are more or less prominent in different 
racial groups or between genders.  For example, bone density is higher and 
the risk for low bone mass and osteoporosis is lower in African American 
women than in Caucasian women.  Both men and women experience osteoporosis, 
but women are at higher risk due to relatively sharp changes in hormonal 
levels associated with menopause.  Older African American men are at higher 
risk for prostate cancer than Caucasians.  Distribution and metabolism of 
adipose tissue are associated with risk of metabolic disease; these differ in 
obese menopausal African American, American Indian and Caucasian women.  The 
molecular underpinnings of these differences in age-related changes need to 
be identified.

The Biology of Aging Program, Neuroscience and Neuropsychology of Aging 
Program, and Geriatrics and Clinical Gerontology Program at the NIA encourage 
applications that will elucidate the basic biological causes and consequences 
of changes in tissue and organ function related to aging and identify 
commonalities, distinguishing features, and interactions between them.  The 
Biology of Aging Program supports work through the Cardiovascular Biology, 
Endocrinology, Immunology, Musculoskeletal Biology, and Physiology Programs.  
These programs encompass most tissues and organs of the body, outside of the 
nervous system.  The Neuroscience and Neuropsychology of Aging Program 
supports work on the nervous system, including fundamental neuroscience, 
integrative neurobiology, motor and sensory systems, cognition and the 
dementias of aging, particularly Alzheimer's disease.  The Geriatrics and 
Clinical Gerontology Program supports research on health and preventing and 
treating disease in the aged, as well as research on aging over the human 
life span and its relationship to health outcomes.  As all of these programs 
cover a broad spectrum of research, areas mentioned in the paragraphs above 
are examples and are not intended to limit the possible areas of research 
support requested in response to this announcement.

Objectives and Scope

This Program Announcement is to intended encourage basic research into 
processes that lead to altered function of tissues and organs as a result of 
aging.  Research that takes maximal advantage of emerging genetic, genomic 
and proteomic information on humans and other animals to understand changes 
that occur with aging is particularly encouraged.  The following examples 
illustrate areas of research that are of interest, but serve as examples 
only, and are not exclusive.  Research projects that focus on various aging 
tissues or physiological systems and how aging of those tissues affects 
function of other tissues, including skin and liver, cardiovascular, 
musculoskeletal, immune, urogenital, endocrine gastrointestinal and nervous 
systems, are of interest.  Basic biology studies on aging that use animal 
models or human tissue are of interest.  However, clinical studies in humans, 
beyond collection of tissues or cells for in vitro use, are outside the scope 
of this Program Announcement.

Examples of possible research areas are given below.  These are examples only 
and are not intended to limit possible areas of research support.  Applicants 
are encouraged to contact the programs listed in this announcement for 
further information.

o  Changes in cell numbers and function with age and how those changes affect 
function in multiple tissues and organs.  Examples include membrane changes, 
cytoskeletal changes and cell signaling changes that have effects on function 
of multiple tissues.

o  Effects of oxidative damage and mitochondrial dysfunction on aging of 
organs and the tissues that constitute them.
 
o  Age-related changes in extracellular matrix and how these changes affect 
function in multiple tissues and organs.

o  Research to understand how decline in function of particular tissues with 
age relates to or causes decline in function of physically interacting 
tissues or organs.  For example, how changes in articular cartilage affect 
underlying bone or how changes in the vascular system affect the brain.

o  Interactions between endocrine and/or immune system cells and factors and 
other organ systems and how changes in these interactions alter organ 
function with age.  For example, how endocrine system changes affect 
cardiovascular or nervous system function, and how immune system changes 
affect inflammatory processes in the brain or may alter bone remodeling with 
aging.

o  Age-related changes in insulin secretion and sensitivity and mechanisms 
underlying adipose tissue distribution and its metabolic effects

MECHANISMS OF SUPPORT 

The mechanism of support will be the National Institutes of Health (NIH) 
research program project grant (P01).  Responsibility for the planning, 
direction, and execution of the proposed project will be solely that of the 
applicant.  

Prospective applicants are encouraged to contact program staff regarding 
applicability of their project to this announcement and to the interests of 
the institute prior to submission.

Prospective applicants are also encouraged to contact program staff for 
specific instructions regarding the expectations for multi-component grants 
at the NIA.

Maximum direct costs requested for program projects under this announcement 
should not exceed $1 million per year.  In addition, program staff must be 
consulted for permission to submit any application that exceeds $500,000 
requested direct costs in any year (see below).

This PA uses just-in-time concepts.  

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) 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 Foreign institutions may not apply for P01 support.
o Domestic institutions 

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.  Women, 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:

o Direct your questions about scientific/research issues to:

Frank L. Bellino, Ph.D.
Endocrinology
Physiology
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231 MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email :  bellinof@nia.nih.gov

Jill L. Carrington, Ph.D.
Chief, Systems Branch, Biology of Aging Program
Musculoskeletal Biology
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231 MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010 
Email:  carringtonj@nia.nih.gov

David B. Finkelstein, Ph.D.
Cardiovascular Biology
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231 MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email :  finkelsd@nia.nih.gov

Rebecca A. Fuldner, Ph.D.
Immunology
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231 MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  fuldnerr@nia.nih.gov

Stanley Slater, M.D.
Geriatrics and Clinical Gerontology Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3E327
Bethesda, MD   20892-9205
Telephone:  (301) 496-6761
FAX:  (301) 402-1784
Email:  slaters@nia.nih.gov

Bradley C. Wise, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3C307 MSC 9205
Bethesda, MD   20892-9205
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
Email:  wiseb@nia.nih.gov

o  Direct your questions about peer review issues  to:

Dr. Mary Nekola
Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue
Suite 2C212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-9666
FAX:  (301) 402-0066
Email:  Nekolam@nia.nih.gov

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

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

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.

SUPPLEMENTAL INSTRUCTIONS: Supplemental instructions for completing 
multicomponent applications, including research program project grant 
applications submitted in response to this announcement, are available at the 
following web site: http://www.nia.nih.gov/ResearchInformation/FundingAndTraining/Research
Support/P01Guidelines.htm

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines for 
program project grants, 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 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 institute 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 institute staff that the Institute will accept 
your application for consideration for award; and,

3) Identify, in a cover letter sent with the application, the staff member 
and institute that 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 three 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)

In addition, to prepare for review of the application, submit two additional 
exact photocopies of the application directly to:  

Dr. Mary Nekola
Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C212, MSC 9205
Bethesda, MD  20892-9205  

It is important that you submit two additional copies to the Scientific Review 
Office as requested.  

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 by NIA 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 May 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)

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 

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.

HUMAN EMBRYONIC STEM CELLS (hESC):  Criteria for federal funding of research 
on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review. 

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 No. 93.866 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, RealPlayer, Video or Flash files, see Help Downloading Files.