Role of Oxidative Stress in Diabetic Enteric Neuropathy

描述（由申请人提供）： 糖尿病（DM）是一种常见疾病，全球患病率为5-6%（1）。糖尿病是第四大死亡原因，近2000万美国人患有这种疾病。多达75%的糖尿病患者可能发生胃肠道功能障碍。目前糖尿病胃肠道并发症的治疗选择仅限于刺激胃肠道动力的药物（1）。因此，阐明糖尿病对肠神经元的影响及神经元损伤的病理生理机制具有重要意义。我们之前已经表明，DM与肠神经元凋亡的增加和含nNOS的肠神经元在体外和体内的损失有关（2）。肠神经元的缺失在糖尿病神经病变的发病机制中起重要作用。初步数据表明，这些神经元的损失可能是继发于氧化应激增加。NF？B与糖尿病神经病变的发病机制有关，氧化应激可以通过多种机制触发NF-κ B的激活。活性氧物质可以触发NF κ B活化的机制之一是通过表面Toll样受体（TLR）的活化，其继而触发降解IKB并激活NF κ B的信号传导事件（3）。为了确定TLR是否具有调节肠神经元存活的作用，我们使用TLR激动剂进行了初步实验。初步数据显示通过TLR的活化导致肠神经元损伤的证据。本提案的总体目标是描述氧化应激在糖尿病肠神经病变发病机制中的作用。氧化应激可导致TLR的改变和NF κ B途径的激活，从而导致神经元细胞死亡。因此，抗氧化剂[原文如此]可能有助于减少这种神经病变。具体目标（有初步数据支持）遵循以下假设：

DESCRIPTION (provided by applicant): Diabetes mellitus (DM) is a common disorder and has a worldwide prevalence of 5-6% (1). DM is the fourth leading cause of death by disease and nearly 20 million Americans have this disease. Gastrointestinal dysfunction may occur in as many as 75% of diabetic patients. Current treatment options for diabetic gastrointestinal complications are limited to include drugs that stimulate gastrointestinal motility (1). Therefore, it is important to elucidate pathological changes in the enteric neurons affected by DM and the pathophysiological mechanisms of neuronal injury. We have previously shown that DM is associated with an increase in enteric neuronal apoptosis and loss of nNOS containing enteric neurons both in vitro and in vivo (2). The loss of enteric neurons plays an important role in the pathogenesis of diabetic neuropathy. Preliminary data shows that the loss of these neurons may be secondary to increased oxidative stress. NF?B has been implicated in the pathogenesis of diabetic neuropathy, and oxidative stress can trigger the activation of NFKB through several mechanisms. One of the mechanisms that reactive oxygen species can trigger activation of NFKB is through activation of the surface Toll like receptors (TLRs) which in turn trigger signaling events that degrade IKB and activate NFKB (3). To determine if TLRs have a role in modulating enteric neuronal survival, we performed preliminary experiments using agonists of TLRs. Preliminary data shows evidence of enteric neuronal damage by activation of TLRs. The overall goal of the present proposal is to characterize the role of oxidative stress in the pathogenesis of diabetic enteric neuropathy. Oxidative stress may lead to alteration in TLRs and activate of the NFKB pathway resulting in neuronal cell death. Antioxidants, [sic] may thus help decrease this neuropathy. The specific aims (supported by preliminary data) follow the hypothesis stated below: [sic]