MOLECULAR STUDIES OF EXPERIMENTAL DIABETIC NEUROPATHY

描述（改编自申请人的摘要）：超过50%的 糖尿病患者有勃起功能障碍，伴有自主神经病变 扮演着近端的角色。然而，自主神经的精确贡献 糖尿病性勃起功能障碍的神经病变仍不明确。的一部分 难以确定自主神经系统的病因作用 糖尿病性勃起功能障碍与阴茎 具有多种机制来保持合胞组织的功能。在 特别是，以下因素之间的相互作用：1.神经元支配，2.细胞-至-细胞 沟通，3。肌源性细胞内信号转导过程， 关键是要保证勃起功能在广泛的生理范围内， 条件这种可塑性被认为是一种对人类生存至关重要的器官。 男人和他们的性伴侣的物种和生理健康。 这些研究的明确目的是利用已建立的大鼠模型， 实验性糖尿病神经病变，以评估糖尿病对 阴茎的自主神经支配，以及发生在阴茎中的任何相关变化， 细胞间通讯和肌源性反应。特别是要 检验自主神经病变与全身性 组织功能的改变，至少部分是由于 在离子流通过钾（K）和间隙连接通道。我们特别 应在Fischer-344中诱导1-6个月的链脲佐菌素（STZ）-糖尿病 （F-344）大鼠，和：1.评估分子变化的功能相关性 与实验性糖尿病相关的K通道和缝隙连接 神经病变/高血糖症，和2.为了评估的功能相关的 K通道和缝隙连接的分子变化，由一种新的 勃起功能障碍的基因治疗方法本 最后，我们将利用从体内动物研究，通过在 组织、细胞、亚细胞和分子/遗传学的体外研究 程度.通过运用如此多样化的技术， 我们希望尽可能深入了解的重要医学问题 在体内的功能相关的良好量化的分子改变。

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.