Up to 1% of all human infants are born with some form of genitourinary abnormality, with a large proportion of them having involvement of the urinary bladder. Abnormal structure and/or function of the bladder results in significant morbidity, including infections, incontinence and even renal insufficiency. Because of its clinical significance, we have begun to study the molecular basis of organogenesis of the urinary bladder. Organogenesis requires the orderly execution of programs that regulate temporally and spatially defined cellular differentiation and proliferation. Surprisingly very little is actually known about the events that occur during normal bladder organogenesis. This is in part due to the lack of an appropriate experimental animal model with which to study the development of the fetal bladder. The long term goal of this proposal is to elucidate the molecular basis of urinary bladder organogenesis in vertebrates, using Xenopus as an experimental system. In our preliminary experiments, we have demonstrated that Xenopus is an ideal model for this proposal since the urinary bladder develops in the larval stage and can be readily accessed. Additionally, we have discovered that the Uroplakin family of genes is expressed very early in embryogenesis and bladder organogenesis. This is significant because Uroplakins have long been considered markers of terminal urothelial differentiation. This proposal seeks to extend our understanding of the molecular regulation of bladder organogenesis, and the role that Uroplakin plays in this developmental pathway with the following specific aims: (1) Identify and characterize the genes involved in bladder organogenesis;(2) Examine the mechanism(s) by which the genes identified in specific aim 1 regulate bladder organogenesis;(3) To determine the function of the Uroplakin genes in early embryogenesis and bladder organogenesis. Through these studies, the candidate will delineate the signal transduction pathways that regulate bladder organogenesis. The results of this proposal will significantly broaden our insights into bladder development, growth, regeneration and response to injury. This knowledge will be utilized to enhance the outcomes of current therapeutic interventions and improve the quality of life for patients with congenital or acquired bladder dysfunction.
