The theme of our Program focuses on studying the differential control of smooth muscle cell tone in physiologically distinct organ systems. A multidisciplinary approach will ensure that information obtained at the cellular and molecular levels will be interpreted in the context of how tissue responses are coordinated in organs in vitro and in vivo. Our hypothesis is that differential organ function, as it relates to myocyte physiology in the bladder and penis, is attributable to quantifiable differences in the way that ionic mechanisms participate in the control of myocyte tone (i.e., contraction and relaxation). Additionally we hypothesize that diabetes-related alterations in neural and/or myocyte physiology will differentially contribute to bladder and erectile dysfunction. To this end, we will use two well-established rat models of diabetic neuropathy, the Streptozotocin (STZ) and BioBreeding Worcester (BB/W), respectively. The Program goal is to obtain a comprehensive functional map of bladder and erectile function, as well as the contribution of diabetic neuropathy/myopathy to urinary incontinence and impotence. Project #1 will evaluate bladder and erectile function and myocyte tone in vivo, in the same animal. Following the in vivo studies, bladder and erectile tissues will be subdivided between Projects 2 to 4. Project #2 will further characterize myocyte tone at the tissue and single cell level. Project #3 will study the properties and regulation of the intercellular transmission of ionic signals among myocyte cell pairs, and their contribution to coordination of myocyte responses. Project #4 will characterize the critical contribution of coordinated myocyte calcium signaling mechanisms via intercellular and extracellular pathways. Cores A & B will provide administrative and animal support services, respectively. Core C will uniquely implement mathematical models for each of the Project components that quantitatively describe and predict the observed distinctions in molecular, cellular, tissue or organ function between the bladder and penis, as well as the effects of STZ-diabetes on these processes. The significance of the Program is that it will delineate mechanisms of differential organ function, shed new insight on the contribution of diabetic neuropathy to commonly observed urologic complications, and suggest novel therapeutic possibilities.
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