PROSTATE GROWTH IN OLDER MEN:  AGE-DEPENDENT MECHANISMS

NIH GUIDE, Volume 22, Number 6, February 12, 1993



PA NUMBER:  PA-93-052



P.T. 34



Keywords:

  Etiology 

  Urogenital System 

  Hyperplasia 

  Biology, Molecular 



National Institute on Aging

National Institute of Diabetes and Digestive and Kidney Diseases

National Cancer Institute



PURPOSE



The National Institute on Aging (NIA) wishes to stimulate basic

research on the etiology of the extraordinarily high incidence of

benign or malignant prostate growth in older men, and issues relative

to clinical consequences and the effectiveness of current and

proposed treatment protocols in older men experiencing pathologic or

symptomatic effects of benign or malignant growth.  The NIA is joined

by other NIH components that support prostate-related research: the

National Institute of Diabetes and Digestive and Kidney Diseases

(NIDDK) supports research into basic prostate biology and benign

prostatic hyperplasia, and the National Cancer Institute (NCI)

supports research into prostate cancer.  The focus of the NIA in

promoting research into ameliorating the negative health effects of

prostate growth in the older male population is on age-related

factors and age-dependent processes of prostate growth.



New and experienced investigators working in the research areas of

prostate cell and molecular biology, prostate biochemistry, clinical

studies of prostate pathology, or related areas are invited to apply

for grant support to study age-related factors and age-dependent

processes in prostate growth that account for the prevalence of these

diseases in older men.



HEALTHY PEOPLE 2000



The Public Health Service (PHS) is committed to achieving the health

promotion and disease prevention objectives of "Healthy People 2000,"

a PHS-led national activity for setting priority areas.  This program

announcement, Prostate Growth in Older Men:  Age-Dependent

Mechanisms, is related to the priority areas of cancer and chronic

disabling diseases.  Potential applicants may obtain a copy of

"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0) or

"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)

through the Superintendent of Documents, Government Printing Office,

Washington, DC 20402-9325 (telephone 202-783-3238).



ELIGIBILITY REQUIREMENTS



Applications may be submitted by foreign and domestic, for-profit and

non-profit organizations, public and private, such as universities,

colleges, hospitals, laboratories, units of State and local

governments, and eligible agencies of the Federal government.

Applications from minority individuals and women are encouraged.

Applicants for K and F awards must be U.S. citizens, non-citizen

nationals, or have been lawfully admitted for permanent residence at

the time of award.  Foreign institutions are not eligible to apply

for R29, K08, or K11 awards.



MECHANISM OF SUPPORT



Support for this program will be by research project grants (R01),

First Independent Research Support and Transition (FIRST) awards

(R29), Clinical Investigator Awards (K08), Physician Scientist Awards

(K11), Individual Postdoctoral Fellowships (F32), Senior Postdoctoral

Fellowships (F33), and conference grants (R13).  The anticipated

average direct cost award for a research project grant is $150,000

per year.



RESEARCH OBJECTIVES



Background



Prostate hyperplasia/hypertrophy (benign or malignant) affects

virtually all men by the age of 80, with an increased incidence

starting between 30 and 40 years of age.  Not all prostate growth

requires clinical treatment; yet the extremely high prevalence of

this disease with advancing age requires a special research focus to

explore the age-dependent mechanisms involved.



Prostate growth is substantial during adolescence, reaching a plateau

about age 25.  Resumption of prostate growth later in life (about age

50) can lead to benign prostatic hyperplasia (BPH), the most common

nonmalignant proliferative abnormality found in any internal organ.

BPH alone occurs in over 75 percent of men over 50 years of age,

reaching 88 percent prevalence by the ninth decade, frequently with

clinical symptoms of outlet obstruction that can lead to bladder wall

hypertrophy, increased risk of urinary infection, and chronic renal

disease.  Surgery, hospitalization and other treatment for BPH are

estimated to cost over a billion dollars per year.  Prostate cancer,

which increases faster with aging than any other form of cancer, is

the most common cancer in U.S. males, and the second leading cause of

cancer death in men, resulting in over 30,000 deaths per year.  Older

black males have a significantly higher rate of prostate cancer than

older white males.  This disease also requires over a billion dollars

per year in surgery and hospitalization costs.



Goals of the program



The purpose of this program announcement is to stimulate research

into the cause(s) of, and treatments for, the extremely high

incidence and prevalence of both benign and malignant prostate growth

in older men, using animal and cell culture models, and human tissue

samples and clinical studies where applicable.  It is imperative that

applicants address age-related issues important to prostate growth

processes.  What is it about aging processes and the properties of

the prostate, its environment, and its natural history that promote

growth?  What are the effects of long term treatment protocols for

BPH and prostate cancer in older men?



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.



o  Molecular genetics/cytogenetics:  Is there an increasing tendency

for molecular and cytogenetic changes (e.g., oncogene activation,

tumor suppressor gene inactivation) with increasing age that are

relevant to prostate growth?



o  Environment/nutritional:  Are there environmental/nutritional

changes, such as decreased production of vitamin D, that combine with

normal aging processes to promote prostate growth?



o  Cell biology:  What is the role of aging processes in programmed

cell death and its abrogation by steroids in promoting prostate

growth; what is the effect of aging on stem cell proliferation that

may lead to prostate growth; what is the effect of aging on

angiogenesis within hyperplastic prostate tissue; is there an

age-dependence in prostate neuroendocrine cell proliferation

associated with prostate growth; are age-dependent processes involved

in the increased invasive/metastatic potential of hyperplastic

prostate cells; are there changes in prostate stromal-epithelial

interactions with aging that lead or predispose to prostate growth?



o  Hormones/growth factors:  Are there age-related changes in

sensitivity of prostatic epithelial or stromal cells to hormones or

growth factors; what is the role of prolactin in promoting prostate

growth and are there age-related changes in prolactin secretion

pertinent to prostate growth; what age-related changes in growth

factor secretion, sensitivity, and paracrine/autocrine interactions

affect prostate growth?



o  Clinical issues of treatment:  How appropriate are current

clinical treatment regimens for prostate growth in older men; are

there prophylactic treatment regimens to minimize the occurrence of

prostate growth with age, such as use of tamoxifen, or retinoids;

what are the effects of long term hormonal treatment (e.g., Proscar

(finasteride), anti-androgens, LHRH agonists) in older men; how

effective, prognostic and specific are prostate specific antigen

(PSA) measurements in older men?



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF MINORITIES IN CLINICAL RESEARCH

STUDY POPULATIONS



The inclusion of women is usually standard terminology for all grants

and contracts: however, due to the specific subject of this program

announcement, i.e., prostate growth, the inclusion of women is not

applicable.  However, the inclusion of minorities remains relevant.



NIH policy is that applicants for NIH clinical research grants and

cooperative agreements are required to include minorities in study

populations so that research findings can be of benefit to all

persons at risk of the disease, disorder or condition under study;

special emphasis must be placed on the need for inclusion of

minorities in studies of diseases, disorders and conditions which

disproportionately affect them.  If minorities are excluded or

inadequately represented in clinical research, particularly in

proposed population-based studies, a clear compelling rationale must

be provided.



The composition of the proposed study population must be described in

terms of racial/ethnic group.  In addition, racial/ethnic issues

should be addressed in developing a research design and sample size

appropriate for the scientific objectives of the study.  This

information must be included in the form PHS 398 in Sections 1-4 of

the Research Plan AND summarized in Section 5, Human Subjects.

Applicants are urged to assess carefully the feasibility of including

the broadest possible representation of minority groups.  However,

NIH recognizes that it may not be feasible or appropriate in all

research projects to include representation of the full array of

United States racial/ethnic minority populations (i.e., Native

Americans (including American Indians or Alaskan Natives),

Asian/Pacific Islanders, Blacks, Hispanics).  The rationale for

studies on single minority population groups must be provided.



For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology,

prevention (and preventive strategies), diagnosis, or treatment of

diseases, disorders or conditions, including but not limited to

clinical trials.



The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded.  However,

every effort should be made to include human tissues from

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.



For foreign awards, since the definition of minority differs in other

countries, the applicant must discuss the relevance of research

involving foreign population groups to the United States'

populations, including minorities.



If the required information is not contained within the application,

the review will be deferred until the information is provided.



Peer reviewers will address specifically whether the research plan in

the application conforms to these policies.  If the representation of

minorities in a study design is inadequate to answer the scientific

question(s) addressed AND the justification for the selected study

population is inadequate, it will be considered a scientific weakness

or deficiency in the study design and will be reflected in assigning

the priority score to the application.



All applications for clinical research submitted to NIH are required

to address these policies.  NIH funding components will not award

grants or cooperative agreements that do not comply with these

policies.



APPLICATION PROCEDURES



This is an ongoing program announcement.  Applications for R and K

awards are to be submitted on the grant application form PHS 398

(rev. 9/91) and will be accepted at the standard application

deadlines as indicated in the application kit.  Individual

Postdoctoral Fellowship National Research Service Award (NRSA) (F32,

F33) applications must be submitted on grant application form PHS 416

(rev. 10/91), and will be accepted on the standard deadlines for that

mechanism.



Application kits are available at most institutional offices of

sponsored research and may be obtained from the Office of Grants

Inquiries, Division of Research Grants, National Institutes of

Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone

301/496-7441.  The title and number of this announcement (PA-93-52,

Prostate Growth in Older Men:  Age-Dependent Mechanisms) must be

typed in Section 2a on the face page of the application.



Applications for F32, F33 and R29 awards must include at least three

letters of reference attached to the face page of the original

application.  Applications submitted without the required number of

reference letters will be considered incomplete and will be returned

without review.



The completed original application and five legible copies must be

sent or delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



REVIEW PROCEDURES



Applications will be assigned to the appropriate initial review group

and funding component on the basis of established Public Health

Service referral guidelines.  The review criteria are the traditional

criteria appropriate to each mechanism.  In accordance with the

standard NIH peer review procedures, research project grant (R01,

R29) and fellowship (F32, F33) applications will be reviewed for

scientific and technical merit by an appropriate study section in the

Division of Research Grants.  All other applications will be reviewed

by review groups of the appropriate funding component.  Following

scientific-technical review, the applications will receive a

second-level review by the appropriate national advisory council.



AWARD CRITERIA



Applications will compete for available funds with all other approved

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  Program balance among research areas within the individual funding

components



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.



Direct inquiries regarding NIA programmatic issues in basic research

to:



Frank Bellino, Ph.D.

Biology of Aging Program

National Institute on Aging

Gateway Building, Suite 2C231

Bethesda, MD  20892

Telephone:  (301) 496-6402

FAX:  (301) 402-0010



Direct inquiries regarding NIA programmatic issues in clinical and

disease-oriented research to:



Sheryl Sherman, Ph.D.

Geriatrics Program

National Institute on Aging

Gateway Building, Suite 3E327

Bethesda, MD  20892

Telephone:  (301) 496-6761

FAX:  (301) 402-1784



For programmatic issues related to the NIDDK, direct inquiries to:



Leroy M. Nyberg, Jr., Ph.D., M.D.

Director, Urology Program

National Institute of Diabetes and Digestive and Kidney Diseases

Westwood Building, Suite 3A-05

Bethesda, MD  20892

Telephone:  (301) 496-7133

FAX:  (301) 402-0223



For programmatic issues related to the NCI, direct inquiries to:



Andrew Chiarodo, Ph.D.

Division of Cancer Biology, Diagnosis and Centers

National Cancer Institute

Executive Plaza North, Suite 316

Bethesda, MD  20892

Telephone:  (301) 496-8528

FAX:  (301) 402-0181



Direct inquiries regarding fiscal matters to:



Mr. Joseph Ellis

Grants Management Officer

National Institute on Aging

Gateway Building, Suite 2N212

Bethesda, MD  20892

Telephone:  (301) 496-1472

FAX:  (301) 402-2945



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic

Assistance No. 93.866.  Awards are made under authorization of the

Public Health Service Act, Title IV, Part A (Public Law 78-410, as

amended by Public Law 99-158, 42 USC 241 and 285) and administered

under PHS grants policies and Federal Regulations 42 CFR 52 and 45

CFR Part 74.  This program is not subject to the intergovernmental

review requirements of Executive Order 12372 or Health Systems Agency

review.



.

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