Painful versus Insensate Diabetic Neuropathy

描述(由申请人提供)：导致糖尿病神经病变(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发挥作用，包括神经营养供应减少，胰岛素支持异常，以及氧化应激。这些症状也可能是特定感觉神经元亚群的外周轴突损伤的基础。我们的长期目标是了解糖尿病肾病疼痛和/或无感觉并发症的病因，这些并发症与胰岛素支持、氧化应激和外周轴突变性有关。这一建议的中心假设是，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的发病机制。目的1研究1型(STZ-A/J vs.STZ-C57BL/6)和2型(ob/ob vs.db/db)糖尿病小鼠痛性和麻木感神经病变的进展，并测试神经营养素能否减轻糖尿病所致的机械敏感性异常。目标2将测试胰岛素支持是否在这些不同的糖尿病小鼠模型中疼痛或麻木感神经病变的进展中起关键作用。目的3将研究氧化应激在这些糖尿病小鼠痛性或麻木性神经病变发展中的作用。目的4将确定对表皮轴突的不同损伤是否是发生痛性或麻木性糖尿病神经病变的重要因素。总而言之，这些研究将确定导致患者体内症状不同进展的三种可能机制，并确定针对糖尿病患者症状严重程度的新治疗目标。 公共卫生相关性： 这项建议将阐明糖尿病神经病变小鼠模型中疼痛症状与非疼痛症状发展的相关机制。将研究神经营养因子、胰岛素支持、氧化应激和轴突变性的作用，以确定导致糖尿病相关神经并发症的机制。

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.