Mitochondrial SOD as a Target for Diabetic Neuropathy

描述(由申请人提供)： 为了响应申请DK-05-011，题为糖尿病并发症动物模型协会(AMDCC)的申请，来自当前AMDCC神经病变表型核心的研究人员提议开发两种新的糖尿病神经病变(DN)小鼠模型，目标是氧化应激的生化途径。我们的总体策略是在2型糖尿病的遗传模型中加速葡萄糖介导的神经元氧化损伤。虽然许多基因产物参与了这一过程，但我们将重点针对参与超氧化物歧化作用的两种酶：线粒体超氧化物歧化酶2(SOD2)和过氧化氢酶(CAT)。我们最初的方法将集中于在易感遗传背景下开发2个Cre-loxP模型。同时，我们提出了两个假说驱动的特定目标，以发现糖尿病肾病的基本病理生理机制。目的1验证感觉神经元过氧化氢酶活性降低将使这些神经元对葡萄糖介导的损伤更敏感的假说。目的2验证糖尿病肾病动物模型具有周围神经系统氧化应激增加的形态和生化标记物的假设。从这项应用中获得的信息将导致对糖尿病肾病发病机制的新见解，并允许开发这种致残并发症的更相关的小鼠模型。 与公共卫生相关：2000万美国人患有糖尿病，发病率每年以5%的速度增长。虽然糖尿病肾病是一种常见且高度病态的疾病，但除了糖尿病本身的控制之外，没有治疗糖尿病肾病的方法。我们的研究将确定治疗糖尿病肾病的细胞靶点，并有可能使所有糖尿病患者受益。

DESCRIPTION (provided by applicant): In response to the request for applications DK-05-011, entitled Animal Models of Diabetic Complications Consortium (AMDCC), the Investigators from the current AMDCC Neuropathy Phenotyping Core are proposing to develop 2 new mouse models of diabetic neuropathy (DN) targeting the biochemical pathways of oxidative stress. Our general strategic approach is to accelerate glucose-mediated oxidative injury in neurons in genetic models of type 2 diabetes. While many gene products participate in this process, we will concentrate on targeting 2 enzymes involved in superoxide detoxification: mitochondrial superoxide dismutase 2 (SOD2) and catalase. Our initial approach will concentrate on developing 2 Cre-loxP models on a susceptible genetic background. In parallel, we propose 2 hypothesis-driven specific aims for discovering the basic pathophysiologic mechanisms underlying DN. Aim 1 will test the hypothesis that decreased catalase activity in sensory neurons will make these neurons more susceptible to glucose-mediated injury. Aim 2 will test the hypothesis that animal models with DN have morphological and biochemical markers of increased oxidative stress in the peripheral nervous system. Information gained from this application will lead to new insights into the pathogenesis of DN and allow for the development of more relevant murine models of this disabling complication. Relevance to Public Health: 20 million Americans are diabetic and the incidence is increasing by 5% each year. Although DN is a common and highly morbid condition, there are no treatments for DN outside of control of the diabetic condition itself. Our studies will identify cellular targets for treatment of DN and have the potential to benefit all patients with diabetes.