Bladder Wall Remodeling Following Alteration of Urothelial Structure (PI, Pamela S. Howard, Ph. D.).
Urothelium plays an important role in the physiology of the detrusor smooth muscle. The effect of PBOO on urothelial structure has not been studied in details. In the proposed research program, we will determine if detrusor smooth muscle receptor expression (P2X, M1-5, and adenosine) and contractility are altered in wild-type and uroplakin II (UPII) knock-out bladders (in collaboration with Dr. Tung-Tien Sun at New York University). In Project 2, we will also determine if release of signaling molecules from the urothelium may augment or attenuate the contractile response in UPII knock-out and wild-type bladders. It is not known if the expression of uroplakin and urothelial basement membrane and structure are altered in UPII wild-type and knock-out bladders, and in normal mice subjected to partial bladder outlet obstruction. Recent studies have elucidated a role for the urothelium in cross-talk with sensory afferent nerves in the sub-urothelial space. However, little is known concerning the effect of signaling molecules produced by the urothelium in controlling detrusor muscle function. This project will seek to determine if the urothelium and the absence of uroplakins can alter contractile responses of detrusor smooth muscle. We will determine if uroplakins are down regulated and the urothelial basement membrane is physically altered as a result of partial bladder outlet obstruction, and also in response to uroplakin ablation. These studies will provide further insight into the molecular mechanisms responsible for the pathologies associated with lower urinary tract diseases and may lead to the development of therapeutic regimes and strategies to alleviate these conditions.