Mitochondrial SOD as a Target for Diabetic Neuropathy

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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.