MOLECULAR PATHWAY TO BLADDER DYSFUNCTION

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DESCRIPTION (Adapted from the Applicant's Abstract): Benign prostatic hyperplasia is chronic an debilitation human condition that is common in aging men. The disease is associated with an abnormal progressive benign overgrowth of the prostate gland that is initiated in middle age. This abnormal prostate growth increases the resistance of the bladder outlet and over time, leads to major alterations in bladder mass, tissue composition, capacity, compliance, and response to pharmacological agents. Over the past 6 years, the laboratories of Robert Levin and Ralph Buttyan have collaborated in the study of animal models of partial bladder outlet obstruction. This collaboration has resulted in a series of scientific publications that describe some important genetic components that we believe are directly involved in the development of a dysfunctional bladder. These studies have led to our hypothesis that bladder ischemia subsequent to partial outlet obstruction is the underlying stimulus for the initiation and progression of changes in the bladder that ultimately results in bladder dysfunction. Our proposed studies will test this hypothesis, and are directed at identifying the cellular/genetic mechanisms that control the transition of the partially obstructed rabbit bladder through 3 distinct phases ultimately leading to the development of severe bladder dysfunctions similar to those observed with human BPH. Specifically, 1. We will determine if overdistension is a prerequisite for the increase in bladder mass, contractile dysfunctions, and genetic responses observed during the initial period following partial outlet obstruction. 2. We will identify the genetic signals that end the first phase of bladder response to partial outlet obstruction (hypertrophy) and initiate the entry into the second phase of bladder response (compensation). 3. We will monitor the extent of hypoxia associated with partial bladder outlet obstruction. As well, we will assay the partially obstructed rabbit bladder for the presence of genetic and other molecular markers of ischemia. 4. We will directly compare the sequence and characteristics of the genetic response to partial outlet obstruction with that of acute onset diuresis. Acute onset diuresis results in a significant increase in bladder mass with increases in the contractile responses to all forms of stimulation.