Benign prostatic hyperplasia (BPH) is a major cause of morbidity from urinary obstruction in the adult male. The standard management of BPH involves transurethral resection of the prostate to alleviate the obstructions. Over 5 billion dollars per annum are expended on the treatment of BPH in North America, resulting in considerable interest in non-surgical methods for the treatment of the disease. Androgens are required for the development of BPH, however the factors which initiate and regulate the growth of BPH in the adult prostate have not been adequately elucidated. In this context, our laboratory has identified a nerve growth factor (NGF)-like peptide secreted by stromal cells, and a corresponding receptor system in the adjacent epithelial cells which regulates paracrine interactive growth in the human prostate. In order to further understand the regulation of the growth of the prostate as it applies to BPH we have initiated studies on the NGF-like peptide and receptors in the human prostate using cell culture and organ culture systems with BPH cell lines and tissue. Specifically, this research proposal contains three primary objectives. The first specific aim is to investigate the role of steroids, known promoters and regulators of BPH, on cell proliferation and the production of the NGF-like peptide in two stromal cell lines, one of which is derived from BPH tissue and the other cell line is derived from normal human prostate tissue. The second specific aim is to investigate the expression of NGF-like receptors in BPH tissue. NGF-like peptides interact with the cell surface through a receptor complex consisting of a 75 kD protein which is thought to modulate the activity of a 140 kD phosphotyrosine kinase receptor, which in turn mediates signal transduction upon the binding of the NGF-like peptide. We have observed either a lack or diminished expression of the 75 kD regulatory component of the receptor complex in BPH tissues. This has led to our hypothesis that in BPH tissue a defect in expression of the 75 kD protein eliminates modulation of the 140 kD phosphotyrosine kinase leading to uncontrolled growth of the epithelial cells. In order to investigate this hypothesis we will further examine the expression of the 75 kD and 14 kD receptor proteins in microsomal fractions of BPH tissue as well as the post-transcriptional expression of the 140 kD phosphotyrosine kinase using molecular probes which hybridize by Northern blot. In the third specific aim we will use organ culture techniques to investigate the interaction between the NGF-like peptide and steroids in modulating the balance between cell proliferation and cell death within BPH tissue. Hence, by using cell culture, organ culture, endocrinological, biochemical and molecular biological techniques we may gain new insights into the role of NGF-like peptides and the corresponding receptor complex in the paracrine interactions between stromal cells and epithelial cells during the regulation of BPH growth.
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