ENDOTHELIAL DYSFUNCTION IN HUMAN DIABETIC NEUROPATHY

人类糖尿病神经病的内皮功能障碍

• 批准号: 6311193
• 负责人: CHARLENE E HAFER-MACKO
• 金额: $ 19.85万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6311193
• 关键词: biopsy; clinical research; diabetic neuropathy; glycation; human subject; immunocytochemistry; in situ hybridization; microcirculation; pathologic process; peripheral nervous system; plasminogen activator; plasminogen activator inhibitors; thrombomodulin; vascular endothelium

DESCRIPTION (Applicant's abstract): Diabetes mellitus remains a leading cause of neurological morbidity (1). In particular, neuropathy affects 60-70% of diabetics and has no effective treatment options. Though the precise mechanisms underlying human diabetic neuropathy are not established, significant research indicates nerve ischemia as a final common pathway. Numerous clinical and experimental studies show impaired vascular endothelial fibrinolysis and antithrombotic regulatory mechanisms, factors inked to diabetes, are important predictors for increased risk of vascular events and ischemic stroke. Furthermore, in vitro studies suggest that key regulatory proteins for both native endothelial fibrinolysis and antithrombotic function may be reduced by metabolic and inflammatory consequences of advanced glycosylation end stage product deposition (AGE's) in blood vessels. Yet, no prior studies have examined whether these same thrombosis regulatory mechanisms are important in the pathogenesis of diabetic neuropathy. Our preliminary data shows that tissue plasminogen activator (tPA) is absent from a substantial proportion of endoneurial vessels in diabetic nerves, but not controls. We also found that thrombomodulin (TM), an endothelial membrane receptor that deactivates thrombin and accelerates activated protein C formation (APC, anti-thrombotic enzyme), is essentially absent in diabetic nerve microvessels, but present in all controls. This biopsy based case-control study tests the hypothesis that key vascular endothelial proteins that regulate fibrinolysis and the TM-Protein C mechanisms are deficient in diabetic nerve microvasculature, constituting a distinct prothrombotic profile compared to non-diabetic control nerves, and that these deficiencies are related to neuropathy severity and the deposition of advanced glycation endproducts; (AGES) in the microvessel wall. Specific aims are to determine (a) whether tPA and TM expression are reduced and plasminogen activator inhibitor-1 (PAI-1) increased, by immunohistochemistry and in situ hybridization, on epi-, peri-, and endoneurial vessels in the microcirculation of diabetic peripheral nerve compared to age-sex matched non-diabetic controls, (b) whether alterations of tPA, PAI-1 or TM expression in nerve microvessels or plasma are greater in individuals with more severe clinical, electrophysiological and neuropathological rating scores, and or (c) related to AGE deposition on nerve microvasculature. Results of this proposal will establish the requisite mechanistic relationships between AGE-mediated endothelial based prothrombotic changes and clinical diabetic neuropathy severity to better understand hyperglycemia induced nerve injury and develop pharmacological and genetic strategies to reduce morbidity associated with this common disorder.

描述（申请人的摘要）：糖尿病仍然是主要原因 神经系统发病率（1）。特别是，神经病会影响60-70％ 糖尿病患者，没有有效的治疗选择。虽然是精确的机制 基本的人类糖尿​​病神经病没有建立大量研究 表示神经缺血是最终的公共途径。许多临床和 实验研究表明，血管内皮纤维蛋白溶解和 抗血栓性调节机制，糖尿病的因素很重要 预测血管事件和缺血性中风风险增加的预测因素。 此外，体外研究表明，这两者的关键调节蛋白 天然内皮内皮纤维蛋白溶解和抗血栓性功能可能会通过 晚期糖基化终阶段的代谢和炎症后果 血管中的产品沉积（年龄）。但是，没有先前的研究 检查了这些相同的血栓性调节机制在 糖尿病神经病的发病机理。我们的初步数据表明组织 纤溶酶原激活剂（TPA）不存在很大一部分 糖尿病神经中的内色血管，但不能控制。我们还发现 血栓形成蛋白（TM），一种内皮膜受体，可失活凝血酶 并加速活化的蛋白C形成（APC，抗凝血酶）， 本质上不存在糖尿病神经微血管，但在所有控件中都存在。 这项基于活检的病例对照研究检验了关键血管的假设 调节纤维蛋白溶解和TM蛋白C机制的内皮蛋白 缺乏糖尿病神经微举行，构成一个独特的 与非糖尿病对照神经相比，促血栓性概况 缺陷与神经病的严重程度和高级沉积有关 糖基化末期； （年龄）在微血管壁上。具体目的是 确定（a）TPA和TM表达是否降低和纤溶酶原 激活剂抑制剂1（PAI-1）通过免疫组织化学和原位增加 在微循环中的表演，周日和内膜容器上进行杂交 与年龄匹配的非糖尿病对照相比，糖尿病周围神经的神经 （b）神经微血管中TPA，PAI-1或TM表达的改变还是 在临床更严重的个体中，血浆更大， 电生理和神经病理学评分评分，或（c） 神经微脉管系统的年龄沉积。该提议的结果将 建立年龄介导的必要的机械关系 基于内皮的促血栓形成变化和临床糖尿病神经病 严重程度更好地了解高血糖诱发神经损伤并发展 降低与此相关的发病率的药理和遗传策略 常见障碍。