Age-associated benign prostatic hyperplasia (BPH) is a major health problem of elderly men. The molecular etiology of BPH is complex and not clearly understood. Chronic influence of multiple regulatory factors including androgen and peptide growth factors are suspected to contribute to pro static cell proliferation and pathogenesis. The species-specific nature of BPH and the lack of an appropriate mouse model have impeded progress in the delineation of the causal factors for the development of BPH and testing of potential intervention strategies. It is our hypothesis that prostate-specific overexpression of the androgen receptor (AR) and insulinlike growth factor-1 (IGF- 1) in transgenic mice would cause increased prostatic cell proliferation and would give rise to a pathological condition similar to human BPH. The first specific aim of this proposal is to generate transgenic mice overexpressing AR in the prostate targeted by a ten kilobase pair long homologous mouse probasin gene promoter and to characterize the age-and androgen-dependent changes in the prostatic morphology, cellular composition and gene expression profiles. Region (proximal, intermediate and distal)- and lobe-specific histopathologic changes during aging will be correlated with gene expression profiles determined by micro array analysis. In the second specific aim, we will elucidate the interacting role of AR and IGF-1 in promoting aberrant cell proliferation and gene expression through comparative analysis of monotransgenic mice with individual prostatic overexpression of AR and IGF- 1 and bitransgenic mice with simultaneous overexpression of both AR and IGF- 1 in the prostate. Our preliminary results support the feasibility of the proposed experiments and successful completion of this study is expected to provide important new insights into the cellular and molecular pathways that lead to the development of the prostatic hyperplasia under the influence of physiological stimuli. Additionally, the transgemc model and molecular markers generated through these investigations will be beneficial for future studies concerning the development of effective intervention strategies and progression/remission of the disease process.
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