This is a revised proposal of the training and research program to support Dr. Firouz Daneshgari for a mentored clinical scientist development award (K08). The proposal will address the pathophysiology of urinary incontinence and voiding dysfunction (UI and VD). UI and VD is a significant and growing medical, social and financial problem in the U.S. Diabetes mellitus (DM), bladder outlet obstruction (BOO), and many other common pathologic conditions with UI and VD, with idiopathic, neuropathic and obstructive etiologies, cause similar structural and possible molecular changes with resultant dysfunction of the lower urinary tract (LUT) smooth muscle/tissue. In many tissues of human and animals, protein kinase C (PKC) has been recognized as a prominent intracellular signaling pathway that mediates responses to various physiologic stimuli and pathologic injuries. PKCmodulates both acute changes in tissue, as well as chronic adaptive changes that can lead to growth, apoptosis or differentiation. The global scientific goal of this application is to interrogate the relationships between DM (a transgenic rat model of type-I like DM), BOO, and chronic parasympathetic blockade and LUT function as assessed by alterations in contractile and relaxing responses detected by in vivo, in vitro, and LUT specific PKC isoforms profile. We propose that the pattern of LUT dysfunction in BOO or diabetes in rat will be replicated by chronic parasympathetic blockade. We further hypothesize that uropathic or mechanical causes of LUT dysfunction will be characterized by alteration in spatial and temporal profile of intracellular LUT protein kinase C isoforms. Base on an outstanding tract record, in both training new investigators and in scientific accomplishments, two groups of experienced scientists at UCHSC, headed by Dr. Alden H. Harken, and at UTSW, headed by Dr. John D. McConnell, will guide and assist Dr. Daneshgari in the development of necessary and sufficient scientific and technical skills to accomplish the specific aims of this application. These groups are uniquely qualified to study the LUT dysfunction and to track altered LUT cell receptor signals into the cystosolic milieu in the normal and abnormal rat. The ultimate goals of this application are : I) to identify intracellular signal transduction events and their mechanism(s) of action, in the LUT, at major transitional events. Replication of PKC isoform profiles among the experimentally pathologic conditions will serve as the mechanistic basis for targeting future treatment strategies, II) to provide the opportunity for Dr. Daneshgari to become an independent investigator in the field of UI and VD, and III) to encourage and to facilitate recruitment of new scientists and new investigative methods, from other fields of biomedical sciences, into the area of investigative urology.
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