application) Erectile dysfunction and bladder dysfunction are prevalent problems associated with diabetes. These debilitating problems often progress throughout a patient's life span and are irreversible. Despite their common occurrence, the mechanisms by which the diabetes related urological problems develop are not well studied or understood. The focus of our application is to investigate the mechanisms of erectile and bladder dysfunction during diabetes progression, an to devise rational and innovative therapeutic strategies to intervene. A key mediator of both vascular and genitourinary smooth muscle function is nitric oxide (NO). Under normal physiological conditions, NO acts as a critical signal transduction agent in these tissues, serving as the primary controller of local erectile responses and urinary sphincter control. Recent studies have shown that superoxide anion destroys NO, reduces its efficacy as a signal transduction agent, and promotes the formation of peroxynitrite, a highly reactive intermediate known to cause nitration of protein associated tyrosine residues and cellular oxidative damage. Thus, loss of NO control may impair signal transduction pathways, cause enzyme inactivation, and induce cellular apoptosis and/or necrosis. Since diabetes is associated with elevated oxidant conditions in both blood and tissues, dysregulation of NO (particularly a shift from """"""""good effects"""""""" to toxicological consequences) may be an important mechanisms for the developing urological dysfunction. Here biochemical and molecular measures of NO production and destruction pathways will be related to erectile and bladder dysfunction and apoptosis during experimental diabetes progression.
Our aims are: 1) test the hypothesis that NO dysregulation participates in erectile dysfunction during experimental diabetes; 2) test the hypothesis that diabetes induced bladder dysfunction is related to modulation of NO production and/or destruction within bladder and/or urethral sphincter smooth muscle; 3) test the hypothesis that cellular apoptosis is a contributor to diabetes induced urological dysfunction; and (4) rationally design and test experimental therapeutic strategies for the prevention or reversal of diabetes induced urological complications, including small molecules and gene therapy. These collaborative investigations will provide important new insights regarding the mechanisms of and treatment options for an emerging health problem. These studies will also contribute valuable basic understanding of erectile and bladder physiology and pharmacology, and the participation of NO in disease.
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