VENULAR ENDOTHELIUM AND DIABETES

小静脉内皮和糖尿病

• 批准号: 2141658
• 负责人: JOHN Peter MORDES
• 金额: $ 18.61万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-05-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2141658
• 关键词: T lymphocyte; antiinflammatory agents; autoantibody; autoimmune disorder; carrageenan; electron microscopy; enzyme linked immunosorbent assay; gene expression; genetic strain; hematopoietic growth factor; insulin dependent diabetes mellitus; laboratory rat; macrophage; pancreatic islet function; pathology; prostaglandins; silicates; vascular endothelium permeability; western blottings

Our long-term objective is to understand the role of vascular endothelium in the pathogenesis of auto-immune insulin-dependent diabetes mellitus (IDDM). Expression of IDDM depends on many factors that we view as analogous to tumblers in a lock. These include the target beta cell, effector and regulatory immunocytes, humoral factors, genetics, environment, and pancreatic endothelial cells (EC). Work performed during the previous grant period has increased our understanding of the endothelial tumbler. We now know that the pancreatic endothelium of rats susceptible to IDDM is prone to abnormal leakiness, in part dependent on a prostaglandin mediated interaction between the EC and macrophages. We have also shown that effector T cells and EC interact in a costimulatory fashion before there is morphological evidence of insulitis, and recently we discovered that anti-EC antibodies capable of inducing abnormal permeability are also generated in advance of insulitis. We hypothesize that EC dysfunction contributes to the pathogenesis of IDDM by disrupting vascular integrity, by enhancing mononuclear cell adherence, or by generating inflammatory cytokines. This hypothesis will be tested in the RT6-depleted DR rat, a well characterized animal model of human IDDM. Specific Aim #1 is to determine in vitro the mechanisms by which EC-T cell interactions lead to EC dysfunction. We will identify the antigens induced on pancreatic EC, analyze EC interaction with relevant T cell subsets, and seek to identify T cell populations capable of suppressing EC activation. Specific Aim #2 is to evaluate the hypothesis that anti-pancreatic EC antibodies contribute to IDDM. We already know that anti-EC antibodies not only precede the onset of insulitis but can also induce abnormal pancreatic vascular leakiness. The biochemical and physiological properties of these antibodies, as well as their in vivo an in vitro activities, will be defined. Specific Aim #3 is to identify in vivo the mechanisms by which EC dysfunction contributes to IDDM pathogenesis in the BB rat. This aim is premised on the fact that BB rat EC leak abnormally and are the target of autoantibodies. We will emphasize electron microscopic analysis of EC pathology and quantitative measurements of EC activation. Our ultimate goal is to understand the importance of the pancreatic endothelium as an initiator or abettor of IDDM. The results of these studies should define the critical role of islet EC in diabetes pathogenesis, uncover the mechanisms by which EC dysfunction contributes to the progression of islet pathology, and suggest what therapies might arrest the process and ultimately prevent the disease.

我们的长期目标是了解血管内皮的作用 自身免疫性胰岛素依赖型糖尿病的发病机制 （IDDM）。 IDDM 的表达取决于许多因素，我们认为 类似于锁中的弹子。 这些包括目标β细胞， 效应和调节免疫细胞、体液因素、遗传学、 环境和胰腺内皮细胞（EC）。 完成的工作 在上一个资助期间增加了我们对 内皮滚筒。 我们现在知道大鼠的胰腺内皮细胞 易受 IDDM 影响，容易出现异常泄漏，部分取决于 前列腺素介导 EC 和巨噬细胞之间的相互作用。 我们 还表明效应 T 细胞和 EC 在共刺激中相互作用 在出现胰岛素炎的形态学证据之前就很流行，最近 我们发现抗EC抗体能够诱导异常 渗透性也在胰岛炎发生之前产生。 我们假设 EC 功能障碍导致了以下疾病的发病机制： IDDM 通过破坏血管完整性、增强单核细胞 粘附，或通过产生炎症细胞因子。 这个假设将 在 RT6 耗尽的 DR 大鼠（一种特征明确的动物模型）中进行测试 人类IDDM。 具体目标#1是确定体外机制 EC-T 细胞相互作用导致 EC 功能障碍。 我们将确定 胰腺 EC 上诱导的抗原，分析 EC 与 相关的 T 细胞亚群，并寻求鉴定有能力的 T 细胞群 抑制 EC 激活。 具体目标#2 是评估 抗胰腺 EC 抗体导致 IDDM 的假设。 我们 已经知道抗 EC 抗体不仅出现在 胰岛炎还可以诱发异常的胰腺血管渗漏。 这些抗体的生化和生理特性，以及 将定义它们的体内和体外活性。 具体目标 #3 是确定体内 EC 功能障碍的机制 有助于 BB 大鼠的 IDDM 发病机制。 这一目标的前提是 BB 大鼠 EC 异常泄漏并成为目标的事实 自身抗体。 我们将重点介绍 EC 的电子显微镜分析 EC 激活的病理学和定量测量。 我们的最终目标是了解胰腺的重要性 内皮细胞作为 IDDM 的引发者或教唆者。 这些结果 研究应确定胰岛 EC 在糖尿病中的关键作用 发病机制，揭示 EC 功能障碍的机制 胰岛病理学的进展，并提出可能的治疗方法 阻止这一过程并最终预防疾病。