Cyclooxygenase Pathway and Diabetic Neuropathy

描述（由申请方提供）：糖尿病周围神经病变（DPN）存在于高达50%的糖尿病患者中，是糖尿病（D）最具威胁性的并发症之一，是非创伤性截肢的主要原因。到目前为止，还没有一种可行的治疗人类DPN的方法。尽管对DPN的病理生理学仍知之甚少，但氧化应激增加和环氧合酶（考克斯）通路活性改变以及前列腺素代谢的后续扰动已被视为关键因素。本申请的总体假设是，在实验D中，氧化应激对考克斯-2途径的激活有助于DPN的生化、功能、神经营养和结构缺陷。本研究的目的是阐明糖尿病周围神经病变发病机制中葡萄糖介导的氧化应激、考克斯通路的组成部分和受损的神经营养支持之间的关系。了解这些机制及其相互关系，可能为使用考克斯-2选择性抑制剂作为DPN患者新的有效治疗方法提供理论基础。将采用链脲佐菌素糖尿病（STZ-D）大鼠、考克斯-2基因表达缺陷的小鼠和考克斯抑制干预。将通过运动和感觉神经传导速度（NCV）和神经血流量（NBF）的功能测量;光镜和电镜神经形态测定;神经能量代谢、氧化应激和抗氧化防御的生化参数;许旺细胞和感觉神经元凋亡（AP）的测量来评估实验性DPN。具体目标是： 目标1.描述葡萄糖介导的氧化应激与考克斯-2通路激活在STZ-D大鼠中选定的生化、功能、形态测量和神经营养缺陷发展中的关系。 目标2.确定人考克斯-2基因缺陷的STZ-D小鼠中选定的生化、功能、形态学、凋亡和神经营养缺陷的发展时间进程。这些研究将有助于阐明氧化应激和考克斯通路影响DPN发展的机制，并有助于设计旨在预防或逆转DPN的人体研究。

DESCRIPTION (provided by applicant): Present in up to 50 % of diabetic patients, diabetic peripheral neuropathy (DPN), is one of the most threatening complications of diabetes mellitus (D), constituting the leading cause of non-traumatic amputations. To date, a viable treatment for human DPN is not available. Although the pathophysiology of DPN is still quite poorly understood, increased oxidative stress and alterations in cyclooxygenase (COX) pathway activity, with subsequent perturbations in prostanoid metabolism, have been involved as critical factors. The overall hypothesis of this application is that in experimental D activation of the COX-2 pathway by oxidative stress, contributes to the biochemical, functional, neurotrophic and structural deficits of DPN. The objective of this proposal is to delineate the relationships between glucose-mediated oxidative stress, components of the COX pathway, and impaired neurotrophic support in the pathogenesis of DPN. Understanding these mechanisms and their relationship, may provide a rationale for the use of COX-2 selective inhibitors as a new and efficient therapeutic approach in patients with DPN. Streptozotocin-diabetic (STZ-D) rats, mice deficient in the expression of the COX-2 gene, and intervention with COX inhibition will be employed. Experimental DPN will be assessed with functional measurements of motor and sensory nerve conduction velocity (NCV) and nerve blood flow (NBF); light and electron microscopic nerve morphometry; biochemical parameters of nerve energy metabolism, oxidative stress, and antioxidative defense; measures of Schwann cell and sensory neuron apoptosis (AP). The Specific Aims are: Aim 1. To characterize the relationships of glucose-mediated oxidative stress to COX-2 pathway activation on the development of selected biochemical, functional, morphometric and neurotrophic defects in STZ-D rats. Aim 2. Determine the time course for the development of selected biochemical, functional, morphometric, apoptotic and neurotrophic defects in STZ-D mice deficient in the human COX-2 gene. These studies will help to elucidate the mechanism by which oxidative stress and COX pathway influence the development of DPN and, facilitate the design of human studies, in which the aim will be the prevention or reversal of DPN.