Benign prostatic hyperplasia (BPH) and prostate cancer occur commonly in the aging male population and significantly affect both the quantity and quality of life. Despite recent advances in the detection and treatment of both diseases, the underlying molecular pathophysiology of benign and malignant prostatic growth remains unclear. The current proposal will extend extensive collaboration between individuals in a variety of clinical and basic science departments at UT Southwestern. The past accomplishments of our group include development of a canine model for BPH, discovery of dihydrotestosterone (DHT) as the primary prostatic androgen, biochemical description of 5 alpha-reductase deficiency, cloning of the human androgen receptor (AR) and 5 alpha-reductase genes, and leadership in the design and conduct of prostatic disease clinical trials. A """"""""critical mass"""""""" of coordinated investigators now permits an expansion of our research agenda. The proposed O'Brien Research Center would fund a Core facility as well as three new projects. The projects outlined in the current proposal bring new investigators, well established in other areas of research, into the field of prostate disease, to explore new basic ideas that may have important clinical applications. The proposed Core facility will function to retrieve and store tissues from surgical and biopsy specimens from patients with both BPH and prostate cancer, in addition to coordinating two small-scale clinical studies designed to test hypothesis related to gen regulation in the human prostate. Project 1 will focus on the molecular genetics of 5 alpha-reductase expression in BPH and prostate cancer, and, utilizing differential polymerase chain reactions (PCR), clone genes whose expression is altered in prostate cancer. Project 2 will characterize AR expression in benign and malignant prostates, correlate expression with biologic and clinical progression, and explore the regulation of AR expression in both tumor cell lines and surgical specimens. Project 3 will characterize contractile protein gene expression in the human prostate, and determine whether androgenic or alpha-adrenergic signals regulate expression of contractile protein genes. These studies are likely to provide significant insight into the biology of benign and malignant prostatic growth.
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