AGE-RELATED PROSTATE GROWTH: BIOLOGIC MECHANISMS (R01 and R21)

RELEASE DATE:  June 25, 2002

PA NUMBER:  PA-02-116

EXPIRATION DATE:  July 15, 2005, unless reissued. 

National Institute on Aging (NIA)
 (http://www.nia.nih.gov/)
National Cancer Institute (NCI)
 (http://www.cancer.gov) 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
 (http://www.niddk.nih.gov)
National Institute of Environmental Health Sciences (NIEHS)  
 (http://www.niehs.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  

Substantial data currently exist showing that prostate volume increases with 
age in middle-aged and older men, following a post-pubertal plateau.  In 
addition, the incidence and prevalence of prostate disease increase with age, 
and are very high in elderly men.  The National Institute on Aging (NIA), the 
National Cancer Institute (NCI), the National Institute of Diabetes and 
Digestive and Kidney Diseases (NIDDK), and the National Institute of 
Environmental Health Sciences (NIEHS) invite research applications addressing 
biologic mechanisms related to aging processes that underlie the initiation 
and progression of prostate growth processes in middle-age, and the 
pathophysiologic connections of that growth process with the prostate 
diseases prevalent in older men, benign prostatic hypertrophy (BPH) and 
prostate cancer.

RESEARCH OBJECTIVES

Background:  Men experience a high probability of clinical and sub-clinical 
prostate-related problems as they grow older, most frequently urinary 
retention related to BPH and/or prostate cancer.  Epidemiologic data suggest 
that, in contrast to most body organs, the prostate gland continues to grow 
and may reach peak growth rates in middle-aged men.  Very little is known, 
however, about what regulates this age-related growth process, and the 
relationship of this growth process with the growth-related prostate problems 
of BPH and cancer.  A health disparity issue also exists here whereby older 
men of African American descent have a substantially higher risk for prostate 
cancer, but not BPH, than older Caucasian men. 

To further explore the epidemiologic and clinical data associated with age-
related prostate growth, and to examine potential biologic processes 
regulating this growth process, the National Institute on Aging, the National 
Institute of Diabetes and Digestive and Kidney Diseases, the National 
Institute of Environmental Health Sciences, and the National Cancer Institute 
sponsored the NIH Workshop on Prostate Growth and Aging, held September, 
2000, in Leesburg, VA.  The conference summary of that workshop has been 
published (Brown TR, Lee C. 2001.  Conference Summary on Prostate Growth and 
Aging, 13-15 September 2000.  The Prostate  48: 54-65).

Goals of this program:  The purpose of this program announcement (PA) is to 
stimulate research into the biologic mechanisms responsible for regulating 
prostate growth processes in middle-age, and its relationship to the 
extremely high incidence and prevalence of both benign and malignant prostate 
growth in older men.  This research may utilize appropriate animal and cell 
culture models, as well as human tissue specimens.  To be responsive to this 
PA, applicants must address age-related issues involved in prostate growth 
processes.  For example, aging-related biologic processes include age-changes 
in bioregulator (e.g., hormones, growth factors, cytokines) levels, tissue 
response to bioregulators, altered cellular or tissue function as cells 
approach senescence, oxidative damage to DNA, lipids and proteins that affect 
their function, glycation of proteins and other macromolecules, altered DNA 
repair processes, and age-changes in immune function.   What is it about 
aging processes and the properties of the prostate, its environment, and its 
natural history that promote re-initiation of growth in middle-age?  The NIA 
is particularly interested in supporting high quality research focused on 
age-related biologic mechanisms underlying health disparities in prostate 
disease.

Examples of the types of research requested are provided below.  These are 
examples only and are not meant to restrict the types of projects of 
interest, provided the focus is on age-related and age-dependent factors in 
prostate growth, or age-related factors or processes that influence the 
initiation or progression of the prostate diseases common in the elderly. 

Age-dependent changes within specific zones of the human prostate leading to 
prostate growth or related disease, such as cell proliferation vs death 
rates, types of cells (epithelial, stromal, immune, neuroendocrine, etc.) and 
their interactions, co-existence of normal, hyperplastic and neoplastic cells 
within these zones, regulation of telomerase, and quantity or function of 
senescent cells or stem cells

Age-dependent genetic changes (e.g., oncogene activation, tumor suppressor 
gene inactivation) or re-expression of fetal developmental genes regulating 
cellular or mitochondrial function relevant to prostate growth or related 
disease

Age-dependent changes in susceptibility to environmental or 
dietary/nutritional influences to promote prostate growth or related disease, 
including pre- or neonatal exposure to environmental estrogens and related 
factors

Age-dependent changes in circulating or endogenous hormones, their 
metabolism, receptors, or intracellular signaling systems that affect 
prostate growth or function, or in sensitivity or altered gene expression of 
prostatic cells to bioregulatory factors 

Age-dependent changes in content or function of immune cells that may affect 
prostate growth or disease processes

Age-dependent changes in prostate growth processes that may lead to increased 
susceptibility for prostate disease in high-risk populations (e.g., prostate 
cancer in African American men) 

Development, verification and utilization of appropriate model systems, 
including animal models, human organ cultures or xenografts, or intra-or 
interspecies tissue recombinants

The NCI has a special interest in receiving applications that address the 
role of aging tissue microenvironment (stromal cells) in prostate 
carcinogenesis and/or progression.  Examples include (1) studies that focus 
on tumor cell-stroma interactions in prostate cancer and in progression and 
metastasis, (2) the role of aging host stroma and the extracellular matrix, 
and growth factors in the acquisition of androgen independent prostate cancer 
and in organ specific metastasis, and (3) the cooperation among oncogenes, 
tumor suppressor genes and growth factors and their interactions with 
prostatic stromal cells during carcinogenesis and tumor progression.     

MECHANISMS OF SUPPORT 

This PA will use the NIH R01 and R21 award mechanisms.  As an applicant, you 
will be solely responsible for planning, directing, and executing the 
proposed project.  R21 support will be used for exploratory/developmental 
projects for which few preliminary data are available and which address 
highly innovative research. Maximum direct costs may not exceed $100,000 per 
year.  The project period for R21 projects may not exceed two years.  The 
project should be designed to be continued through application for 
unsolicited R01 grants.  R21 grants will not be renewed.

This PA uses just-in-time concepts.  It also uses the modular and non-modular 
budgeting format. (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, use the standard PHS 398 
application instructions.

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:

o Direct your questions about scientific/research issues to:

Frank Bellino, PhD
Biology of Aging Program 
National Institute on Aging 
Gateway Building, Suite 2C231
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email: bellinof@nia.nih.gov

Suresh Mohla, Ph.D.
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard
Rockville, MD 20892
Telephone: (301) 435-1878
FAX: (301) 480-0864
Email: mohlas@mail.nih.gov

Christopher Mullins, Ph.D.
Director, Basic Cell Biology Program, DKUHD
National Institute of Diabetes and Digestive and Kidney Diseases
Two Democracy Plaza, Room 637
6707 Democracy Blvd.
Bethesda, MD 20892
Telephone: (301) 451-4902
FAX: (301) 480-3510
Email: mullinsc@extra.niddk.nih.gov

Michael E. McClure, Ph.D. 
Chief, Organs and Systems Toxicology Branch                         
Division of Extramural Research and Training                            
National Institute of Environmental Health Sciences  
111 T.W. Alexander Drive 
Courier: 79 T.W. Alexander Dr 
P.O. Box 12233, Mail Drop EC-23 
Bldg. 4401, Rm. 3417 
Research Triangle Park, North Carolina 27709 
RTP. NC 27709 
Telephone: (919) 541-5327   
FAX: (919) 541-5064 
Email: mm461n@nih.gov
 
o Direct your questions about financial or grants management matters to:

Jeff Ball
Grants and Contracts Management Office 
National Institute on Aging 
Gateway Building, Room 2N212
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email: ballj@nia.nih.gov

Bill Wells
Grants Administration Branch
National Cancer Institute
6120 Executive Blvd., EPS, Room 243 
Bethesda, MD  20892 
Telephone:  (301) 496-8796 
FAX:  (301) 496-8601
Email:  wellsw@gab.nci.nih.gov

Trude Hilliard
Grants Management Specialist
National Institute of Diabetes and Digestive and Kidney Diseases
Two Democracy Plaza, Room 717
6707 Democracy Blvd.
Bethesda, MD 20892
Telephone: (301) 451-8859
FAX: (301) 480-4237
Email: hilliardt@extra.niddk.nih.gov

Jackie Russell 
Grants Management Specialist
Division of Extramural Research and Training 
National Institute of Environmental Health Sciences 
P. O. Box 12233, EC-22 
111 T.W. Alexander Drive, (for express/courier service) 
Research Triangle Park, NC  27709 
Telephone:  (919) 541-0751
FAX:  (919) 541-2860  
Email:  russell@niehs.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 the 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 all racial and 
ethnic groups (and subgroups) 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 

INCLUSION OF MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that 
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.

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 Nos. 93.866 (NIA), 93.849 (NIDDK), 93.396 (NCI), 
93.866 (NIEHS) and 93.113 (NIEHS) 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 to 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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