UROLOGICAL DYSFUNCTION AND NO CONTROL IN DIABETES

描述（改编自应用程序） 勃起功能障碍和膀胱功能障碍是普遍存在的问题 与糖尿病有关。这些使人衰弱的问题往往会进展 在患者的整个生命周期中，都是不可逆的。尽管他们 常见的发生，糖尿病相关的泌尿系统的机制， 问题没有得到很好的研究或理解。的重点 应用是研究勃起和膀胱的机制， 糖尿病进展期间的功能障碍，并制定合理且 创新的治疗策略进行干预。两者的关键调解人 血管和泌尿生殖器平滑肌功能的一个重要因素是一氧化氮（NO）。 在正常生理条件下，NO作为一种关键信号， 在这些组织中的转导剂，作为主要的控制器， 局部勃起反应和尿道括约肌控制。最近的研究 已经表明，超氧阴离子破坏NO，降低其作为一种 信号转导剂，并促进过氧亚硝酸盐的形成， 已知引起蛋白质硝化的高活性中间体 相关的酪氨酸残基和细胞氧化损伤。因此， NO调控可能会损害信号转导途径，导致酶 失活，并诱导细胞凋亡和/或坏死。以来 糖尿病与血液和血液中氧化剂条件升高有关， 组织，NO的失调（特别是从“良好效果”到 毒性后果）可能是一个重要的机制， 出现泌尿系统功能障碍在这里，生物化学和分子测量 一氧化氮的产生和破坏途径将与勃起和 实验性糖尿病膀胱功能障碍与细胞凋亡 进展我们的目的是：1）测试的假设，NO失调， 参与勃起功能障碍在实验性糖尿病; 2）测试 糖尿病引起的膀胱功能障碍与 调节膀胱内的NO产生和/或破坏，和/或 尿道括约肌平滑肌; 3）检验细胞 细胞凋亡是糖尿病诱导的泌尿功能障碍的促成因素;并且 (4)合理设计和测试实验治疗策略， 预防或逆转糖尿病引起的泌尿系统并发症， 包括小分子和基因治疗。这些协作 调查将提供重要的新见解， 新出现的健康问题的机制和治疗方案。这些 研究还将有助于对勃起和 膀胱生理学和药理学，以及NO参与 疾病

DESCRIPTION (adapted from the 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.