VENULAR ENDOTHELIUM AND DIABETES

我们的长期目标是了解血管内皮细胞的作用 自身免疫性胰岛素依赖型糖尿病的发病机制 (IDDM)。IDDM的表达取决于我们认为的许多因素 类似于锁上的玻璃杯。其中包括靶向的β细胞， 效应器和调节性免疫细胞，体液因子，遗传学， 环境和胰腺内皮细胞(EC)。已完成的工作 在前一个资助期内，增加了我们对 血管内皮细胞转杯。我们现在知道大鼠的胰腺内皮细胞 易患IDDM的人容易出现异常渗漏，部分依赖于 前列腺素介导的内皮细胞和巨噬细胞之间的相互作用。我们 还表明效应器T细胞和EC在共刺激下相互作用 在有形态上的胰岛素炎证据之前，以及最近 我们发现抗EC抗体能够诱导异常 渗透性也是在胰岛炎症之前产生的。 我们推测内皮细胞功能障碍参与了糖尿病的发病机制。 IDDM通过破坏血管完整性，通过增强单个核细胞 粘附性，或通过产生炎性细胞因子。这一假说将 在rt6耗尽的DR大鼠身上进行测试，这是一种具有良好特征的动物模型 人类IDDM的基因。具体目标1是在体外确定其作用机制 其中EC-T细胞相互作用导致EC功能障碍。我们将确定 胰腺内皮细胞诱导的抗原，分析内皮细胞与 相关的T细胞亚群，并寻求识别能够 抑制EC的激活。具体目标#2是评估 假设抗胰腺EC抗体与IDDM有关。我们 我已经知道，抗EC抗体不仅发生在 胰岛炎但也可导致胰腺血管异常渗漏。 这些抗体的生化和生理特性，以及 作为它们在体内和体外的活性，将被定义。特定目标 #3是在体内确定EC功能障碍的机制 在BB大鼠的IDDM发病机制中起重要作用。这一目标的前提是 BB大鼠EC异常渗漏并成为 自身抗体。我们将强调EC的电子显微镜分析 血管内皮细胞活化的病理学和定量检测。 我们的最终目标是了解胰腺的重要性 内皮细胞作为IDDM的启动者或促进者。这些研究的结果 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功能障碍的作用机制 胰岛病理的进展，并建议哪些治疗方法可能 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.