Aging is a major factor that contributes to abnormal growth of the prostate leading to the condition of benign prostatic hyperplasia (BPH) in men. Unlike the human prostate, the rodent prostate is organized into different anatomical lobes referred to as the ventral, dorsal and lateral. Each lobe is biochemically distinct and differentially responsive to androgens. Based upon embryologic origin and biochemical function, the lateral and dorsal lobes have been considered homologous to the human prostate, whereas the ventral lobe lacks homology. Past studies in our laboratory have established that spontaneous and androgen-stimulated prostate epithelial cell hyperplasia occurs in the dorsal and lateral, but not the ventral lobe of aging Brown Norway rats. Hence, the age-dependent, lobe-specific prostatic hyperplasia of Brown Norway rats is considered to be a model for human BPH. Our working hypothesis is that aging contributes to a progressive increase in oxidative stress within the prostate, the consequences of which are alterations in the lobe-specific sensitivity to androgen and alterations in cell regulatory mechanisms. These alterations manifest themselves in the form or reactivated cell proliferation and increased cell survival, with the net effect being cellular hyperplasia. The lobe-specific, age-dependent occurrence of hyperplasia provides a unique model to understand the factors that differentially contribute to hyperplasia. In this application, we propose three aims to determine: 1) if changes in androgen sensitivity alter the expression of cell cycle regulatory molecules that activate cell proliferation leading to hyperplasia; 2) if changes in growth factor regulation and expression increase cell proliferation and survival leading to hyperplasia; and 3) if oxidative stress causes damage to lipids, proteins and DNA that correlates with disruption of normal regulation of prostate growth. These studies should lead to a better understanding of the molecular mechanisms that underlie the incidence of prostatic hyperplasia with increasing age, particularly at a time in life when the androgendependent prostate is exposed to a hormonal milieu with paradoxically diminished testosterone concentration.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG020999-03
Application #
6866404
Study Section
Special Emphasis Panel (ZRG1-UROL (01))
Program Officer
Bellino, Francis
Project Start
2003-05-01
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
3
Fiscal Year
2005
Total Cost
$367,875
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Bethel, Carlise R; Chaudhary, Jaideep; Anway, Matthew D et al. (2009) Gene expression changes are age-dependent and lobe-specific in the brown Norway rat model of prostatic hyperplasia. Prostate 69:838-50
Chen, Haolin; Pechenino, Angela S; Liu, June et al. (2008) Effect of glutathione depletion on Leydig cell steroidogenesis in young and old brown Norway rats. Endocrinology 149:2612-9
Yan, Jinchun; Brown, Terry R (2008) Cell proliferation and expression of cell cycle regulatory proteins that control the G1/S transition are age dependent and lobe specific in the Brown Norway rat model of prostatic hyperplasia. Endocrinology 149:193-207
Pechenino, Angela S; Brown, Terry R (2006) Superoxide dismutase in the prostate lobes of aging Brown Norway rats. Prostate 66:522-35
Chen, Haolin; Luo, Lindi; Liu, June et al. (2005) Aging and caloric restriction: effects on Leydig cell steroidogenesis. Exp Gerontol 40:498-505