Prostatic cell hyperplasia occurs in the dorsal and lateral lobes, but not the ventral lobe, of the aging Brown Norway rat. These findings suggest that androgen sensitivity of the Brown Norway rat prostate is lobe-specific and age-dependent. Therefore, we propose to investigate age-specific changes in the regulation of growth and differentiated cell structure and function in aging Brown Norway rats to elucidate the mechanisms of prostatic hyperplasia.
The specific aims of this proposal are: 1) we will measure serum and tissue concentrations of testosterone (T), and its active metabolites dihydrotestosterone (DHT) and estradiol (E2) and determine whether changes in androgen or estrogen receptors, 5alpha- reductase or aromatase activities occur within each lobe; 2) we will determine whether age-associated intrinsic changes occur within each lobe to affect androgen sensitivity. We will pharmacologically alter androgen receptor binding, 5alpha-reductase activity and DHT levels or aromatase activity and E2 levels in young and old rats and determine whether cell specific structure and function is affected; 3) we will determine whether age-dependent and lobe-specific differences occur in cell death and cell proliferation following castration alone or when androgen is replaced; and 4) we will determine whether lobe-specific cellular hyperplasia is related to age-dependent changes in the magnitude or temporal pattern of testicular testosterone production. Growth within the ventral, lateral and dorsal prostate lobes will be assessed by tissue weight; cell structure by microscopic examination of call morphology and stereologic analysis of cell number within epithelial and stromal compartments; and function by Northern blots of specific mRNAs and Western blots of specific proteins for androgen receptor and 5alpha-reductase in all tissues, for prostate in, dorsal protein I and probasin in the ventral, dorsal and lateral prostate lobes, respectively. Growth factors and their receptors will be related to changes in androgen sensitivity and in cellular morphology. Immunocytochemistry and in situ RNA hybridization will be used to localize cell-specific expression of gene products.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG008321-11
Application #
6424493
Study Section
Project Start
2001-04-01
Project End
2003-03-31
Budget Start
Budget End
Support Year
11
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Jervis, Kathryn M; Robaire, Bernard (2004) The effects of long-term vitamin E treatment on gene expression and oxidative stress damage in the aging Brown Norway rat epididymis. Biol Reprod 71:1088-95
Zubkova, Ekaterina V; Robaire, Bernard (2004) Effect of glutathione depletion on antioxidant enzymes in the epididymis, seminal vesicles, and liver and on spermatozoa motility in the aging brown Norway rat. Biol Reprod 71:1002-8
Anway, Matthew D; Folmer, Janet; Wright, William W et al. (2003) Isolation of sertoli cells from adult rat testes: an approach to ex vivo studies of Sertoli cell function. Biol Reprod 68:996-1002
Ezer, Nadine; Robaire, Bernard (2003) Gene expression is differentially regulated in the epididymis after orchidectomy. Endocrinology 144:975-88
Jervis, Kathryn M; Robaire, Bernard (2002) Changes in gene expression during aging in the Brown Norway rat epididymis. Exp Gerontol 37:897-906
Banerjee, Partha P; Banerjee, Subhadra; Brown, Terry R (2002) Bcl-2 protein expression correlates with cell survival and androgen independence in rat prostatic lobes. Endocrinology 143:1825-32
Chen, Haolin; Hardy, Matthew P; Zirkin, Barry R (2002) Age-related decreases in Leydig cell testosterone production are not restored by exposure to LH in vitro. Endocrinology 143:1637-42
Culty, Martine; Luo, Lindi; Yao, Zhi-Xing et al. (2002) Cholesterol transport, peripheral benzodiazepine receptor, and steroidogenesis in aging Leydig cells. J Androl 23:439-47
Luo, L; Chen, H; Zirkin, B R (2001) Leydig cell aging: steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme. J Androl 22:149-56
Jervis, K M; Robaire, B (2001) Dynamic changes in gene expression along the rat epididymis. Biol Reprod 65:696-703

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