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• 批准号: 3922927
• 负责人: PETER JAMES DYCK
• 金额: --
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3922927
• 关键词: biopsy; blood vessels; diabetes mellitus therapy; diabetic neuropathy; disease /disorder model; disease /disorder proneness /risk; human age group; human subject; human therapy evaluation; human tissue; laboratory rat; peripheral blood vessel disorder; postmortem; sex; vascular smooth muscle nervous control

The main question addressed in this project is, "Do pathologic abnormalities of nerve microvessels play a role in the pathogenesis of diabetic neuropathies?" The studies address which vessels are involved, what are the pathologic processes, at what stage of development of neuropathy and by the influence of which risk factors? Cranial nerves III and VI, lumbosacral roots and systematically sampled levels of peripheral nerves at postmortem, and sural nerve at biopsy, from diabetics with and without neuropathy, and from healthy subjects, are to be studied by neuropathologic and morphom metric approaches to determine the three-dimensional pattern of fiber loss, regeneration and pathologic abnormality characteristic of different diabetic neuropathies. In endoneurial microvessels, the number of endothelial and pericyte muclei and the areas of lumen (LA), endothelial cells (EA), pericytes (PA), basement membrane (BMA), and wall (WA) are to be measured in electron micrographs. In epineurial arterioles, the number if endothelial, intimal and medial nuclei and LA, EA, medial area (MA), and WA are to be estimated in transverse semi-thin epoxy sections using our Imaging System for Nerve Morphometry (ISNM). The type and patterns of fiber pathologic abnormality are to be compared to patterns found in human neuropathies of known cause and especially to experimentally induced models of ischemic injury, neuronal degeneration and diffuse Schwann cell disease. Is the pattern of fiber loss and pathology like that of ischemic injury or of another mechanism? Is the severity of pathologic alterations of epineurial arterioles and endoneurial microvessels associated? Is the severity of pathologic alterations of microvessels associated with fiber pathology? Using serial semi-thin and thin sections the stereologic arrangement of terminal arteriole- capillary-venule (ACV) units are to be reconstructed in control and diabetic nerve looking for altered patterns of vascularization in diabetic neuropathy. Using the characteristics patterns of pathologic alterations found in experimental models of ischemic neuropathy, human diabetic nerves are to be critically studied looking for ischemic cores. If ischemic cores are found, are they found in early neuropathy or only in advanced neuropathy? Non- diabetic neuropathies are also to be studied assessing for specificity of vascular lesions in diabetic neuropathy. To search for insights as to cause of vessel and fiber alteration in diabetic neuropathy, pathologic alterations of vessels and fibers will be induced in rats by: a) ambient hypoxia, b) arterial ligation, c) microsphere embolization, d) single and mulitple nerve crush, e) lead neuropathy, and f) toxic and genetically induced diabetes.

在这个项目中解决的主要问题是，"做病理学 神经微血管异常在神经元损伤中发挥作用 糖尿病神经病变的发病机制？"这些研究涉及 涉及哪些血管，病理过程是什么， 神经病变的发展阶段以及 哪些风险因素？ 颅神经III和VI，腰骶神经根 并对周围神经进行系统采样， 尸检和活检的腓肠神经，来自糖尿病患者， 没有神经病变，并从健康受试者进行研究 通过神经病理学和形态计量学方法来确定 纤维损失、再生和 不同类型糖尿病的病理异常特点 神经病 在神经内膜微血管中， 内皮细胞和周细胞核以及管腔面积（LA）， 内皮细胞（EA），周细胞（PA），基底膜（BMA）， 和壁（WA）在电子显微照片中测量。 在 神经外膜小动脉，内皮、内膜和 内侧核和LA，EA，内侧区（MA）和WA将被 在横向半薄环氧树脂截面中使用我们的 神经形态测量成像系统（ISNM）。 的类型和 纤维病理异常的模式将与 在已知原因的人类神经病中发现的模式， 特别是实验诱导的缺血性损伤模型， 神经元变性和弥漫性雪旺细胞病。 是 纤维损失和病理学模式，如缺血性损伤或 另一种机制？ 病理改变的严重程度 神经外膜小动脉和神经内膜微血管的关系 微血管病理改变的严重程度 与纤维病理学有关吗 使用串行半薄和薄 切片显示终末小动脉的体视学排列， 毛细血管-微静脉（ACV）单位将在控制下重建 和糖尿病神经寻找改变的血管化模式 糖尿病性神经病变 使用的特征模式 缺血性脑血管病实验模型中发现的病理改变 神经病变，人类糖尿病神经将被严格研究 寻找缺血核心 如果发现缺血核心， 发现于早期神经病变还是仅发现于晚期神经病变？ 非 糖尿病神经病变也将被研究， 糖尿病神经病变血管病变的特异性。 搜索 了解糖尿病患者血管和纤维改变的原因， 神经病变，血管和纤维的病理改变将是 通过以下方法在大鼠中诱导：a）环境缺氧，B）动脉结扎，c） 微球栓塞，d）单个和多个神经挤压，e） 铅性神经病，和f）中毒性和遗传性糖尿病。