We propose to further investigate the pathophysiological role and the potential diagnostic therapeutic relevance of the insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) in benign prostatic hyperplasia (BPH). Over the past several years, we have elucidated an intricate network of molecular interactions of IGFs and related molecules in the prostate. We have shown that IGFs, IGF receptors, IGFBPs and IGFBP proteases are all present in prostatic cells, tissues, and fluids, and provide an important growth regulatory system. We have identified several IGF-related abnormalities in prostatic stromal cells (PC-S) from BPH tissues. One of these is the under-expression of WT-1, a tumor suppressor gene which regulates IGF-II and IGF receptor gene transcription in prostate stromal cells. Abnormal expression of WT-1 in BPH leads to dys-regulated expression of critical components of the IGF growth cascade. We also noted that transforming growth factor-D (TGFD), which has a growth-inhibitory effect on PC-S, dramatically stimulates the production of the growth-inhibitory IGFBP-3 in PC-S derived from normal but not BPH tissues. We thus hypothesize that the prostatic stroma is the site of the primary molecular defect in BPH and that this defect involves dys-regulated IGF and IGFBP gene transcription at both the basal state and in response to modulating factors. In our proposed studies, we plan to address the following experimental goals: 1) To further characterize the nature of the WT-1 defect and its role in dys-regulation of the IGF axis in BPH by the use of CDNA sequencing and by employing antisense oligomers and CDNA transfection to look for reversion of the molecular and biological phenotype; 2) To identify other molecular abnormalities in BPH stromal cells by differential display and northern analysis of MRNA from normal and BPH sources; 3) To examine the biological effects of molecular abnormalities in IGF axis components and other elements on the phenotype of prostatic stromal cells by evaluating proliferation, apoptosis and differentiation in response to modulating factors (such as TGFD and other regulators); and 4) To use our findings in vitro to identify IGF-related or other (non IGF-related) in situ markers in the tissues of men with BPH. If successful , our findings may provide new targets for drug development and other novel therapeutic interventions or diagnostic strategies for use in men with BPH.
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