Our long term research goals are to understand the role and regulation of apoptosis in the development of benign prostatic hyperplasia (BPH). BPH is a disease of the prostate of aging men. In BPH, the prostate of the aging man undergoes a spontaneous reinitiation of new ductal and stromal tissue growth. In contrast, the normal adult prostate is in a homeostatic state in which the rates of cell proliferation and cell death are balanced to maintain no net growth of the gland. Recent studies suggest that the initial increase in prostate volume occuring with the induction of BPH from the normal prostate is associated with an increased proliferation in epithelial and stromal compartments of the prostate but that the further increase in prostate volume occuring in aging men is not associated with a further increase in cell proliferation rate, but rather with a lack of cellular apoptosis in the prostate stroma. Our hypothesis proposes that there is an imbalance between the rates of cell proliferation and apoptosis in prostate stroma in BPH. In the normal prostate the proliferative and apoptotic rates in the stroma are balanced and with the induction of BPH a graded decline in apoptotic rate occurs. We further propose that the deregulation of apoptosis is mediated by alterations in the expression of apoptotic regulatory proteins expressed by prostate stroma. Furthermore, one mechanism driving the altered expression of apoptotic regulatory proteins is in the change in Testosterone:Estradiol ratio in the aging male. In the present study we will use the human prostate as a model of the role of apoptosis in postatic stroma during aging. Two specific aims are proposed. Aim one will a) measure apoptotic and proliferative rates and the expression of selected apoptotic regulatory proteins in ex vivo prostate tissues and in in vitro cultures of prostate stromal cells derived from patients of varying age and b) determine the effect of changes in T:E ratio on apoptotic and proliferative rates and expression of apoptotic regulatory proteins in prostate stromal cultures in vitro. Aim two will a) establish and characterize an in vivo nude mouse model system of human prostate stromal apoptosis during aging and b) investigate effects of castration and changing T:E ratios on apoptosis, proliferation and expression of apoptotic regulatory proteins in the model system.