(Taken directly from the application) The overall objective of this program project is to develop a team consisting of investigators in the areas of epithelial biology, membrane biosynthesis, carcinogenesis and structural biology, that will interact closely and synergistically to study the cell and molecular biology and diseases of mammalian urothelium. Towards this long term goal, we will perform five interrelated projects focusing on a group of novel integral membrane proteins, the uroplakins, that form the urothelial plaques (also known as the asymmetrical unit membrane) that cover over 80% of the urothelial apical surface. These proteins represent excellent markers for terminally differentiated urothelial cells, and their genes are regulated in a urothelium-specific and differentiation-dependent fashion.
The aims of these five projects are to better understand: o What is the biological function of urothelial plaques, and how are the genes that encode the uroplakins regulated (Project 1)? o Once uroplakins are synthesized, how are they processed, assembled and targeted to the apical urothelial surface (Project 2)? o How do the uroplakin molecules interact with one another to form the 16-nm particles that naturally form two-dimensional crystalline arrays in urothelial plaques (Project 3)? o If we use uroplakin promoters to drive the expression of various oncogenes in urothelia of transgenic mice, what kinds of proliferative defects would we see (Project 4)?
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