AGE-RELATED CHANGES IN TISSUE FUNCTION:  UNDERLYING BIOLOGICAL MECHANISMS

RELEASE DATE:  July 7, 2003

PA NUMBER:  PA-03-147

EXPIRATION DATE:  July 30, 2006, unless reissued. 

National Institute on Aging (NIA)  
 (http://www.nia.nih.gov/)
National Cancer Institute (NCI)
 (http://www.nci.nih.gov/)
National Institute on Deafness and Other Communication Disorders (NIDCD) 
 (http://www.nidcd.nih.gov)
National Institute of Dental and Craniofacial Research (NIDCR)
 (http://www.nidcr.nih.gov/)
National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  93.866, 93.396, 93.173, 
93.121, 93.849

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 OF THIS PA  

This program announcement is to solicit 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 that emphasize molecular 
and cellular changes that are common among tissues with aging are also 
encouraged, as are projects that compare mechanisms of aging change in 
different tissues.  Projects must have a clear relevance to aging to be 
considered under this PA.

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.

The NIDCD, NIDCR, and NIDDK each support research in their respective areas 
of interest.  Applicants can obtain further information for each of the 
sponsoring Institutes at the web addresses listed on the first page of this 
announcement or by contacting the respective program contact listed in this 
announcement.

The NCI is interested in understanding the similarities and differences in 
the "aging" stroma and the stroma associated with malignant epithelial cells 
both in early and later stages of the malignancy.  Experimental results 
indicate that the overall changes in the extracellular matrix/stroma that 
occur during the aging process render it more permissive to supporting tumor 
growth. Within the context of changes in tissue with age that lead to, or are 
permissive of tumorigenesis, areas that are of interest to NCI include: the 
extracellular matrix and cell adhesion molecules, properties or behavior of 
stroma of various tissues such as the breast, prostate, brain, 
gastrointestinal tract, bone etc., aberrant expression of growth factors 
and/or their receptors in the stroma, altered expression of protease as well 
as tissue inhibitors of proteases, response of aging/premalignant stroma to 
hormonal regulation, and changes in the migratory properties of epithelial or 
stromal cells 

Objectives and Scope

This Program Announcement is intended to 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, including skin and liver, cardiovascular, 
musculoskeletal, immune, renal and 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.

A.  Studies on individual tissues/organs:

o  Changes in adult stem cells and their environment that result in altered 
tissue and organ function with age.

o  Age-related changes in regulation of angiogenesis.

o  The role of non-estrogen hormones and bio-regulatory factors separately or 
in combination with estrogen in the development of postmenopausal health 
problems related to particular tissues or organs.

o  Mechanisms of age-related prostate growth in the adult.

o  Homeostatic mechanisms that regulate the size and composition of the T-
cell pool and the naive and memory T-cell subsets with age.  Mechanisms of 
attenuated function of the thymus and factors required to support normal T-
cell differentiation and maturation.

o  Research to identify functionally important polymorphisms in genes that 
lead to changes in function of particular cells and tissues with age.  
Interactions among genes with particular polymorphisms that lead to greater 
or lesser change in function with age.
 
o  Basic biology research to understand gender and/or racial differences 
leading to altered rates or phenotype of change in tissues and organs with 
age.

o  Age-related changes in skin and wound healing.

o  Age-related changes in steroid hormone levels and activity as well as 
activity of tissue-specific hormone-like compounds.

o  Mechanisms of age-related change in the musculoskeletal system, including 
muscle atrophy, development of temporamandibular joint disorders (TMJD), 
altered bone density, and development of osteoarthritis.

o  Age-related changes in the regulation of neurogenesis.

o  Mechanisms underlying age-related changes in cognition and in sleep, motor 
and sensory processes.

o  Research on mechanisms controlling selective vulnerability of brain cells 
and circuits to atrophy and degeneration in normal aging and in 
neurodegenerative disorders.

o  Identification and role of biological risk or protective factors, such as 
steroids, cytokines or neurotrophic factors, in modifying nervous system 
function in aging.

o  Changes in gastrointestinal or hepatic function in aging.

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

o  Age-related changes in kidney function, including the impact of aging on 
both donors and recipients of renal allografts.

o  Age-related changes in gingival tissue and susceptibility to oral 
infections, such as periodontitis.

o  Mechanisms of cellular senescence in the oral epithelium.

B.  Studies on aging changes affecting multiple tissues or organs:

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

o  Effects of oxidative damage and mitochondrial dysfunction on aging of 
multiple 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  Profiling of changes with age in the stroma that are permissive of 
development of malignancies, including head and neck tumors.

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 in 
the aged.

MECHANISM OF SUPPORT 

This PA will use the NIH 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.  This program does not require cost 
sharing as defined in the current NIH Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.  

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 Domestic or foreign
o Faith-based or community-based organizations 

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:

o Direct your questions about scientific/research issues to:

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

Chhanda Dutta, Ph.D.
Geriatrics and Clinical Gerontology Program
National Institute on Aging, NIH, DHHS
7201 Wisconsin Avenue, Suite 3E327
Bethesda, MD   20892-9205
Telephone:  (301) 435-3048
FAX:  (301) 402-1784
Email:  cd23z@nih.gov

Bradley C. Wise, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging, NIH, DHHS
7201 Wisconsin Avenue, Suite 350
Bethesda, MD   20892-9205
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
Email:  wiseb@nia.nih.gov

Suresh Mohla, Ph.D.
Chief, Tumor Biology and Metastasis Branch
Division of Cancer Biology
National Cancer Institute, NIH, DHHS
EPN, Suite 5000
Bethesda, MD  20892
Telephone:  (301) 435-1878
FAX:  (301) 480-0864
Email:  mohlas@mail.nih.gov

Lana Shekim, Ph.D.
Director, Voice and Speech Programs
Division of Scientific programs
National Institute on Deafness and Other Communication Disorders, NIH, DHHS
6120 Executive Blvd., Room 400C
Bethesda, MD 20892-7180
Telephone: (301)-496-5061
Fax: (402)-402-6251
E-mail: shekiml@nidcd.nih.gov

Yasaman Shirazi, PhD
Program Director,
Epithelial Cell Regulation and Transformation Program
Division of Basic & Translational Sciences
National Institute of Dental & Craniofacial Research, NIH, DHHS
National Institutes of Health
45 Center Dr., Rm: 4AN-18C
Bethesda, MD  20892-6402
Tel: 301-594-4812
Fax: 301-480-8318
Email: yasaman.shirazi@nih.gov

Catherine M. Meyers, M.D.
Program Director of Inflammatory Kidney Diseases
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Rm. 641
Bethesda, MD  20892-5458
Telephone:  (301)594-7717
FAX:  (301)480-3510
Email:  cm420i@nih.gov 

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

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

Bill Wells
Section Chief, Biology and Population Sciences Section
Grants Administration Branch
National Cancer Institute, NIH, DHHS
Executive Plaza South, Room 243
6120 Executive Boulevard, MSC 7150
Bethesda, MD 20892-7150
Telephone: (301) 496-8796
FAX: (301) 496-8601
E-mail: ww14j@nih.gov

Sara Stone
Chief, Grants Management Branch
National Institute on Deafness and Other Communication Disorders, NIH, DHHS
6120 Executive Blvd., Room 400B-MSC
Bethesda, MD 20892-7180
Telephone: (301)-402-0909
Fax: (301)-402-1758
E-mail: stones@nidcd.nih.gov

Mary Daley
Chief Grants Management Officer
Division of Extramural Activities
National Institute of Dental and Craniofacial Research, NIH, DHHS
45 Center Drive, Room 4AN-44B
Bethesda, MD  20892-6402
Phone:  (301) 594-4808     
Fax:  (301) 480-3562
Email: md74u@nih.gov

Randi Freundlich, R.D.
Grants Management Specialist 
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases, NIH, DHHS
6707 Democracy Boulevard, Rm. 714, MSC 5456
Bethesda, MD  20892-5456
Telephone: (301) 594-8825
FAX (301) 594-9523
E-mail: rf160d@nih.gov

Ms. Aretina Perry-Jones
Grants Management Specialist
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 745 MSC 5456
Bethesda, MD  20892-5456
Telephone:  (301) 594-8862
FAX:  (301) 480-3504
Email:  ap19s@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 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.  

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  Appropriate scientific review groups 
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 the 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 the application's overall score, weighting them as appropriate 
for each application.  The 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, an investigator may propose to 
carry out important work that by its nature is not innovative but is 
essential to move a field forward.

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

APPROACH: Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project? Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

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

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

ENVIRONMENT: Does the scientific environment in which the 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, the following 
items will be considered in the determination of scientific merit and the 
priority score:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See criteria included in the 
section on Federal Citations, below).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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 will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to 
be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.  

ADDITIONAL CONSIDERATIONS 

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 

HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. 

MONITORING PLAN AND DATA AND SAFETY 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 and Safety 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 "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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
Department of Health and Human Services (DHHS) issued final modification to 
the "Standards for Privacy of Individually Identifiable Health Information", 
the "Privacy Rule," on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR). Those who must comply with the Privacy Rule (classified 
under the Rule as "covered entities") must do so by April 14, 2003  (with the 
exception of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on "Am I a covered 
entity?"  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at 
http://grants1.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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 at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm 

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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