Mitochondrial SOD as a Target for Diabetic Neuropathy

线粒体 SOD 作为糖尿病神经病变的靶标

基本信息

批准号：
7492825
负责人：
Eva Lucille Feldman
金额：
$ 21.71万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7492825
关键词：
Aconitate Hydratase Admission activity Afferent Neurons American Amputation Animal Model Antioxidants Appendix Back Biochemical Markers Biochemical Pathway Blood Vessels Carbohydrates Categories Cellular Structures Citric Acid Cycle Clinical Research Complex Complication Complications of Diabetes Mellitus Condition Defect Development Diabetes Mellitus Diabetic Neuropathies Drug Metabolic Detoxication Electron Transport Electrons Enzymes Event Failure Genetic Genetic Models Genetic Predisposition to Disease Glucose Goals Hospitals Hydrogen Peroxide Hydroxyl Radical Hyperglycemia Incidence Injury Iron Lead Longevity Mediating Membrane Metabolic Mitochondria Modeling Molecular Mus Neuronal Injury Neurons Neuropathy Nitric Oxide Nitrogen Dioxide Non-Insulin-Dependent Diabetes Mellitus Oxidation-Reduction Oxidative Stress Oxygen Participant Pathogenesis Patients Peripheral Nervous System Peroxonitrite Persons Phenotype Positioning Attribute Principal Investigator Process Production Proteins Protons Public Health Reaction Reactive Nitrogen Species Reactive Oxygen Species Request for Applications Research Research Personnel Respiration Rodent Model Role Series Structure Sulfur Superoxide Dismutase Superoxides Susceptibility Gene System Testing United States catalase cellular targeting cost diabetic experience human SOD2 protein human disease improved insight mouse model oligomycin sensitivity-conferring protein oxidation programs response

项目摘要

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.

描述（由申请人提供）：为了响应题为糖尿病并发症动物模型联盟 (AMDCC) 的申请 DK-05-011 的要求，当前 AMDCC 神经病变表型核心的研究人员提议开发 2 种新的糖尿病神经病变 (DN) 小鼠模型，针对生化氧化应激的途径。我们的总体策略是在 2 型糖尿病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这一过程，但我们将重点关注参与超氧化物解毒的 2 种酶：线粒体超氧化物歧化酶 2 (SOD2) 和过氧化氢酶。我们最初的方法将集中于在易感遗传背景上开发 2 个 Cre-loxP 模型。同时，我们提出了 2 个假设驱动的具体目标，以发现 DN 的基本病理生理机制。目标 1 将检验以下假设：感觉神经元中过氧化氢酶活性的降低将使这些神经元更容易受到葡萄糖介导的损伤。目标 2 将检验以下假设：DN 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志物。从该应用中获得的信息将带来对 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，且发病率每年以 5% 的速度增加。尽管 DN 是一种常见且发病率很高的疾病，但除了糖尿病本身的控制外，尚无治疗 DN 的方法。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。