MOLECULAR MECHANISMS OF B-CELL IMPAIRMENT-DESTRUCTION

此应用程序中的项目涉及通过以下机制 在糖尿病综合征中，β细胞受损或被破坏。一个潜在的 其中几个项目的前提是早期损失 两种形式的糖尿病患者的葡萄糖刺激的胰岛素分泌都表明 一种特殊的葡萄糖感应‘装置’的早期损伤。出于这个原因， 在开发过程中将检查各种参数 非自身免疫性疾病，希望将固有的 叛逃。同样，在自身免疫性糖尿病中，一种外质来源的假说 同一β细胞“装置”的组成部分是免疫学的靶标。 攻击将接受测试。葡萄糖转运蛋白(GT)和 葡萄糖激酶(GK)作为葡萄糖感应“装置”的组成部分将被 通过分析这两个基因的表达模式来确定 葡萄糖反应性和非反应性β细胞系中的蛋白质。在一次 在推测的血糖感应器中更远的位置， 葡萄糖，通过升高β细胞中的丙二酰辅酶A和 将氧化后的脂肪酸转移到甘油二酯中， 增加蛋白激酶C的活性；如果是这样，这可能构成 非自身免疫性糖尿病的缺陷部位。胰淀素在植物生长发育中的作用 非自身免疫性糖尿病的胰岛素反应缺陷也将是 仔细检查过。最后，引起自身免疫的近端事件 糖尿病的研究将从自身免疫的概念开始 糖尿病是由淋巴因子传递的β细胞损伤引发的 在常规感染期间从巨噬细胞释放。免疫机制 对β细胞的破坏将在抗体研究中解决。 以及针对β细胞抗原的T细胞和基因 分析由人类白细胞抗原分子决定的IDDM的易感性。

The projects in this application deal with the mechanisms by which beta-cells are impaired or destroyed in diabetic syndromes. An underlying premise in several of the projects is that the early loss of glucose-stimulated-insulin secretion in both forms of diabetes points to an early lesion in a specific glucose-sensing 'apparatus'. For this reason a variety of parameters will be examined during the development of the nonautoimmune disease in the hope of bracketing the site of an intrinsic defect. Similarly in autoimmune diabetes the hypothesis that an exoplasmic component of the same beta-cell "apparatus" is a target of immunologic attack will be tested. The role of the glucose transporter (GT) and glucokinase (GK) as components of the glucose-sensing "apparatus" will be determined by analyzing expression patterns of the genes for these two proteins in glucose-responsive and nonresponsive beta-cell lines. At a more distal site in the putative glucose-sensing apparatus, the possibility that glucose, by elevating malonyl-CoA in beta-cells and diverting fatty acids from oxidation into the diacylglycerol pool, increases protein kinase C activity; if so, this may constitute possible locus of a defect in nonautoimmune diabetes. The role of amylin in the defective insulin response of nonautoimmune diabetes will also be scrutinized. Finally, the proximal events giving rise to autoimmune diabetes will be studied beginning with the concept that autoimmune diabetes is triggered by injury to beta-cells delivered by lymphokines released from macrophages during routine infections. Mechanisms of immune destruction of beta-cells will be addressed in studies of the antibodies and T cells that are directed at beta-cell antigens and the genetic predisposition to IDDM determined by HLA molecules will be analyzed.