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型糖尿病发病机制中的作用 糖尿病(IDDM)。自身免疫性糖尿病的表达 涉及大量的因素，我们认为这与 把玻璃杯锁在一起。这些玻璃杯包括目标测试版 细胞，效应细胞和调节性免疫细胞，体液因子， 胰腺内皮细胞、遗传和环境因素。这个 血管内皮细胞是目前最不为人所知的玻璃杯。它 潜在地起着关键作用，因为1)细胞参与了β 细胞破坏必须定位并穿过胰腺 内皮，2)内皮细胞表达Ia抗原和 呈现经过处理的外来抗原。 对人胰腺静脉内皮细胞的研究是显而易见的 实施起来很困难，因此提出它是合理的 在IDDM的动物模型上进行实验。其中最重要的是 模型是BB大鼠，它与人类的模型非常相似 有一种自身免疫的发病机制，而且已经发现 有局限于胰腺的静脉通透性缺陷。我们 对BB大鼠胰腺小静脉内皮细胞的研究 在接下来的一系列实验中。 第一个特定目标是确定胰腺小静脉的特征 Monastal蓝B色素联合应用对大鼠内皮细胞渗漏的影响 血管标记技术。菌株的特异性，器官 特异性、遗传学和剂量反应曲线将是 下定决心。第二个具体目标是确定哪个因素或 巨噬细胞毒素二氧化硅和 角叉菜胶能完全阻断莫司他蓝引起的血管渗漏 BB鼠。巨噬细胞本身及其分泌产物将 以评估其对静脉渗漏的影响。特定目标 第三项是研究大鼠胰腺小静脉内皮细胞在 体外培养。我们将在培养中鉴定内皮细胞，然后使用 培养的细胞研究Ia激活，淋巴细胞黏附， 以及对体外细胞毒作用的影响。 我们的最终目标是了解胰腺的重要性 小静脉内皮细胞作为自身免疫的启动者或促进者 糖尿病。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取决于 这在一定程度上取决于内皮细胞特有的因素。

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.