VENULAR ENDOTHELIUM AND DIABETES

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 （胰岛素依赖型糖尿病）。 胰岛素依赖型糖尿病的表现取决于许多因素，我们认为， 类似于锁中的制栓。 这些包括目标β细胞， 效应和调节免疫细胞，体液因子，遗传学， 环境和胰腺内皮细胞（EC）。 所做工作业绩 在过去的一段时间里，我们对这个问题的认识有所提高。 内皮细胞 我们现在知道大鼠的胰腺内皮细胞 易患胰岛素依赖型糖尿病的人容易出现异常渗漏，部分取决于 前列腺素介导的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， 时尚之前，有胰岛炎的形态学证据，最近 我们发现抗EC抗体能够诱导异常的 渗透性也在胰岛炎之前产生。 我们假设EC功能障碍有助于 通过破坏血管完整性，通过增强单核细胞 粘附，或通过产生炎性细胞因子。 这一假设将 在RT 6耗尽的DR大鼠中进行测试， 人胰岛素依赖型糖尿病 具体目标#1是在体外确定 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，并寻求鉴定能够 抑制EC激活。 具体目标#2是评估 假设抗胰腺EC抗体导致IDDM。 我们 已经知道抗EC抗体不仅先于 胰岛炎，但也可诱发异常胰腺血管渗漏。 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是在体内确定EC功能障碍的机制， 有助于BB大鼠的IDDM发病机制。 这一目标是坚定不移的。 BB大鼠EC异常渗漏， 自身抗体 我们将着重于EC的电镜分析 EC活化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 内皮细胞作为胰岛素依赖型糖尿病的启动者或教唆者。 的结果予以 研究应明确胰岛EC在糖尿病中的关键作用 发病机制，揭示EC功能障碍有助于 胰岛病理学的进展，并提出什么治疗方法， 阻止这一过程并最终预防疾病。

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.