MOLECULAR STUDIES OF EXPERIMENTAL DIABETIC NEUROPATHY

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DESCRIPTION (Adapted from the Applicant's Abstract): More than 50 percent of patients with diabetes have erectile dysfunction, with autonomic neuropathy playing a proximal role. However, the precise contribution of autonomic neuropathy to diabetic erectile dysfunction remains undefined. Part of the difficulty in establishing the etiologic role of the autonomic nervous system in diabetic erectile dysfunction is related to the fact that the penis is endowed with multiple mechanisms for preserving syncytial tissue function. In particular, the interaction among: 1. neuronal innervation, 2. cell-to-cell communication, and 3. myogenic intracellular signal transduction processes, are critical to guarantee erectile function over a wide range of physiological conditions. Such plasticity is expected of an organ critical to the survival of the species and the physiological well being of men and their sexual partners. The explicit aim of these studies is to utilize an established rat model of experimental diabetic neuropathy to evaluate the effects of diabetes on autonomic innervation in the penis, and any correlative changes that occur in intercellular communication and myogenic responsivity. In particular, we will test the hypothesis that autonomic neuropathy is associated with global alterations in tissue function, that result, at least in part, from alterations in ion flow through potassium (K) and gap junction channels. Specifically, we shall induce a 1-6 month period of streptozotocin (STZ)-diabetes in Fischer-344 (F-344) rats, and: 1. Evaluate the functional correlates of molecular changes in K channels and gap junctions that are associated with experimental diabetic neuropathy/hyperglycemia, and 2. To evaluate the functional correlates of the molecular changes in K channels and gap junctions that are produced by a novel gene therapy approach for the amelioration of erectile dysfunction. To this end, we will utilize techniques ranging from in vivo animal studies, through in vitro studies at the tissue, cellular, subcellular and molecular/genetic levels. By bringing to bear such a diverse array of techniques on this important medical problem we hope to gain the greatest insight possible into the functional correlates in vivo of well quantified molecular alterations.