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.
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