Painful versus Insensate Diabetic Neuropathy

描述（由申请人提供）：导致糖尿病性神经病变（DN）疼痛或麻木症状的机制尚不清楚。许多变量可能在这些不同症状的发展中起作用，包括神经营养供应减少，胰岛素支持异常和氧化应激。这些症状也可能是外周轴突损伤的基础在选择的感觉神经元亚群。我们的长期目标是了解与胰岛素支持、氧化应激和外周轴突变性有关的DN疼痛和/或不敏感并发症的病因。该建议的中心假设是独特的遗传差异是糖尿病神经病变不同进展和严重程度的基础。探索这些遗传差异将有助于确定糖尿病神经病变发病机制。目的1将描述1型（STZ- A/J vs. STZ- c57bl /6）和2型（ob/ob vs. db/db）糖尿病小鼠模型中疼痛和麻木神经病变的进展，并测试神经营养因子是否可以减轻糖尿病诱导的机械敏感性异常。目的2将测试胰岛素支持是否在这些糖尿病小鼠模型中疼痛或麻木神经病变的进展中起关键作用。目的3将检查氧化应激在这些糖尿病小鼠疼痛或麻木神经病变发展中的作用。目的4将确定表皮轴突的不同损伤是否是发生疼痛性或无感觉性糖尿病神经病变的重要因素。总的来说，这些研究将确定三种可能的机制，负责人类患者经历的症状的可变进展，并确定针对糖尿病患者症状严重程度的新治疗靶点。

DESCRIPTION (provided by applicant): The mechanisms that lead to painful or insensate symptoms in diabetic neuropathy (DN) are poorly understood. Many variables likely play a role in the development of these diverse symptoms, including reduced neurotrophic supply, abnormal insulin support, and oxidative stress. These symptoms may also underlie peripheral axon damage amongst select sensory neuronal subpopulations. Our long-term goal is to understand the etiology of painful and/or insensate complications of DN in relation to insulin support, oxidative stress, and peripheral axon degeneration. The central hypothesis of this proposal is that unique genetic differences underlie the differential progression and severity of diabetic neuropathy. Exploring these genetic differences will help identify mechanisms involved in the pathogenesis of diabetic neuropathy. Aim 1 will characterize the progression of painful and insensate neuropathy in type 1 (STZ- A/J vs. STZ-C57Bl/6) and type 2 (ob/ob vs. db/db) mouse models of diabetes and test whether neurotrophins can alleviate the diabetes-induced abnormalities in mechanical sensitivity. Aim 2 will test whether insulin support plays a critical role in the progression of painful or insensate neuropathy amongst these variant mouse models of diabetes. Aim 3 will examine the role of oxidative stress in the development of painful or insensate neuropathy in these diabetic mice. Aim 4 will determine whether differential damage to epidermal axons is important factor in developing painful or insensate diabetic neuropathy. Collectively, these studies will identify three possible mechanisms responsible for the variable progression of symptoms experienced within human patients and identify new therapeutic targets aimed at the severity of symptoms amongst diabetic patients. PUBLIC HEALTH RELEVANCE: This proposal will elucidate mechanisms related to the development of painful versus nonpainful symptoms in mouse models of diabetic neuropathy. The role of neurotrophins, insulin support, oxidative stress, and axonal degeneration will be investigated to identify mechanisms that lead to the neural complications associated with diabetes.