The human prostate is particularly susceptible to dysfunction arising grow cell growth abnormalities. Prostate adenocarcinoma is now the most commonly diagnosed cancer among American men, accounting for about 40,000 deaths per year at current rates Benign prostatic hyperplasia (BPH), a non-malignant neoplastic disorder of the human prostate that inhibits urine flow through the prostatic urethra, affects over 800,000 men per year in the US. A majority of men over the age of 50 will occasionally or persistently suffer from symptoms attributable to BPH, including urinary retention, urinary tract injection, hematuria, and bladder muscle dysfunction. Although abnormal tissue expansion is evident in both epithelial and stromal compartments in PH, symptoms are thought to arise primarily from expansion of the stromal compartment and from other neuromuscular abnormalities. This is a competing renewal of a proposal to study the role of heparin-binding epidermal growth factor-like growth factor (MB-EGF), and related EGF-like factors, in prostate growth. In the first grant period (7/94 through 3/99) we have accumulated significant evidence that HB-EGF is an important growth factor in the adult human prostate, and therefore of potential physiologic relevance to both benign and malignant prostatic disease.. Importantly, we found that (1) HB-EGF is synthesized almost exclusively by smooth muscle cells (SMC) of the interstitital stroma and the vascular bed; and (2) that the membrane form of HB-EGF (""""""""mHB-EGF"""""""", for """"""""membrane HB-EGF"""""""") was most likely the predominant form of the growth factor present in the prostate under steady-state conditions. In the new proposal we will focus on understanding the role of mHB-EGF as a mediator of cell survival and determine whether mHB-EGF or soluble HB-EGF is a physiologic regulator of human prostate smooth muscle cells.
The specific aims of the new proposal are:
Specific Aim 1 : Determine whether unique binding partners of membrane HB-EGF mediate apoptosis and survival signals. We will test the hypothesis that mHB-EGF acts a survival factor independently of the secreted form of the growth factor and that one or more membrane binding partners, including the tetraspan, protein CD9 and the Bcl-2 binding protein, BAG-1, collaborate with mHB-EGF in this survival activity.
Specific Aim 2 : Determine the mechanism of HB-EGF growth and survival regulation of prostate SMC. In these experiments we will determine whether mHB-EGF or sHB-EGF is the predominant growth/survival regulator in this cell type and identify and determine the role of possible collaborating proteins.
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