ROLE OF VENULAR ENDOTHELIUM IN DIABETES

这项建议的长期目标是研究 血管内皮在胰岛素依赖性高血压发病机制中的作用 糖尿病（IDDM）。 自身免疫性糖尿病的表达 涉及大量的因素，我们认为这些因素类似于 锁里的制栓 这些不倒翁包括目标测试版 细胞，效应和调节免疫细胞，体液因子， 胰腺内皮、遗传和环境因素。 的 内皮细胞是目前了解最少的内皮细胞。 它 潜在地起着关键作用，因为1）参与β-细胞 细胞破坏必须定位并穿过胰腺 内皮，和2）内皮细胞表达Ia抗原，和 呈递处理过的外来抗原。 对人类胰腺微静脉内皮的研究显然 很难执行，因此建议合理 在胰岛素依赖型糖尿病的动物模型中进行。 其中， 模型是BB大鼠，它与人类非常相似 在自身免疫发病机制中，已经发现 有局限于胰腺的小静脉通透性缺陷。 我们 研究BB大鼠胰腺微静脉内皮细胞 在接下来的一系列实验中。 具体目标1是表征胰腺小静脉 使用单星蓝B色素和 血管标记技术。 菌株特异性、器官 特异性、遗传学和剂量反应曲线将被 测定 具体目标2是确定哪些因素或 因素是负责巨噬细胞毒素二氧化硅和 卡拉胶完全阻断单星蓝诱导的渗漏 BB鼠 巨噬细胞本身及其分泌产物 评价其对小静脉渗漏的影响。 具体目标 号3.研究大鼠胰腺微静脉内皮细胞在 体外 我们将在培养中表征内皮细胞，然后使用 培养细胞以研究Ia活化，淋巴细胞粘附， 以及对体外细胞毒性的影响。 我们的最终目标是了解胰腺的重要性 微静脉内皮作为自身免疫性疾病的启动者或教唆者 糖尿病的 这些实验应该能让我们确定 如果胰岛素依赖型糖尿病的表达依赖于 部分依赖于内皮细胞特异性因子。

The long-term objective of this proposal is to study the role of the vascular endothelium in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). The expression of autoimmune diabetes involves a large number of factors which we view as analogous to the tumblers in a lock. These tumblers include the target beta cell, effector and regulatory immunocytes, humoral factors, the pancreatic endothelium, genetics, and environmental factors. The endothelium is the least well understood tumbler at this time. It potentially plays a pivotal role since 1) cells involved in beta cell destruction must locate and traverse the pancreatic endothelium, and 2) endothelial cells express Ia antigens and present processed foreign antigen. Studies of pancreatic venular endothelium in humans are obviously difficult to carry out and its is therefore reasonable to propose to perform them in an animal model of IDDM. Foremost among such models is the BB rat which strongly resembles its human counterpart in having an autoimmune pathogenesis, and which has been found to have a venular permeability defect limited to the pancreas. We propose to study the pancreatic venular endothelium of the BB rat in the following series of experiments. Specific Aim No. 1 is to characterize pancreatic venular endothelial leakage in the rat using Monastral blue B pigment and the technique of vascular labeling. The strain specificity, organ specificity, genetics, and dose response profile will be determined. Specific Aim No. 2 is to determine which factor or factors are responsible for the macrophage toxins silica and carrageenan completely block Monastral blue induced leakage in the BB rat. Macrophages themselves and their secretory products will be evaluated for their effects on venular leakage. Specific Aim No. 3 is to study rat pancreatic venular endothelial cells in vitro. We will characterize the endothelia in culture and then use the cultured cells to study Ia activation, lymphocyte adherence, and effects on in vitro cytoctoxicity. Our ultimate goal is to understand the importance of the pancreatic venular endothelium as either an initiator or abettor of autoimmune diabetes mellitus. These experiments should allow us to determine if the expression of insulin dependent diabetes mellitus depends in part on factors specific to endothelial cells.