The human bladder wall responds to increased urethral resistance by changes in cellular composition, generally seen as a hypertrophic increase in smooth muscle mass as well as remodeling of the bladder tissue architecture. These histologic changes accompany functional changes such as increases in residual urine, bladder volume, and voiding pressure. Bladder hypertrophy occurs as a progressive response to urinary outlet obstruction resulting from several conditions, such as benign prostatic hyperplasia (BPH) in men, age-related bladder dysfunction in women, as well as congenital urogenital tract anomalies. BPH symptoms, many of which can now be attributed to bladder dysfunction, arise in greater than 40% of men over the age of 60. Our group has recently accumulated a number of independent lines of evidence that heparin-binding epidermal growth factor-like growth factor (HB-EGF), and at least two ErbB family receptors capable of signaling down-stream from HD-EGF (ErbB1 and ErbB2), are involved in the response of bladder cells to mechanical stimuli. We propose to use an in vitro model of mechanical cell stretch, and in vivo models of complete and partial bladder outlet obstruction, to test the hypothesis that: 1) mechanical forces activate multiple signaling systems in bladder cells; 2) one or more of these pathways is required for a growth response to mechanical signals; and 3) these signaling pathways can be manipulated in ways that alter the bladder's response to outlet obstruction of the urinary tract.
The Specific Aims are: 1) To determine whether bladder cell growth evoked by mechanical stimuli is dependent on activation of the ERK-MAPK, JNK/SAPK or the p38 MAPK phosphorylation cascades. 2) To determine whether bladder cell growth evoked by mechanical stimuli is dependent on ErbB receptor ligands and/or ErbB family receptors. These studies are motivated by a need for newer treatment strategies for obstructive disease, therapies which are based on a more thorough understanding of the underlying pathophysiology of the bladder's response to urinary outlet obstruction. New therapies based on the underlying mechanisms of obstructive uropathy will diminish the need for surgical intervention and improve the quality of life for patients with non-malignant bladder dysfunction.
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