Mitochondrial SOD as a Target for Diabetic Neuropathy

描述（由申请人提供）： 为响应申请DK-05-011（标题为糖尿病并发症动物模型联盟（AMDCC））的请求，当前AMDCC神经病表型核心的研究者提议开发2种新的糖尿病神经病（DN）小鼠模型，靶向氧化应激的生化途径。我们的总体策略是加速2型糖尿病遗传模型中神经元中葡萄糖介导的氧化损伤。虽然许多基因产物参与这一过程，但我们将集中精力靶向参与超氧化物解毒的2种酶：线粒体超氧化物歧化酶2（SOD 2）和过氧化氢酶。我们最初的方法将集中于开发2个易感遗传背景的Cre-loxP模型。同时，我们提出了2个假设驱动的具体目标，发现基本的病理生理机制的基础DN。目的1将检验感觉神经元中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设。目的2将验证DN动物模型具有外周神经系统中氧化应激增加的形态学和生化标志物的假设。从该应用中获得的信息将导致对DN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。 与公共卫生的相关性：2000万美国人患有糖尿病，发病率每年增加5%。虽然DN是一种常见的和高度病态的条件，有没有治疗DN以外的糖尿病病情本身的控制。我们的研究将确定治疗DN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.