MOLECULAR MECHANISMS OF B CELL IMPAIRMENT/DESTRUCTION

本申请中的项目涉及的机制， β细胞在糖尿病综合征中受损或被破坏。下面的 几个项目的前提是， 在两种糖尿病中，葡萄糖刺激的胰岛素分泌表明， 特定葡萄糖传感“装置”的早期损伤。为此 在开发过程中将检查各种参数， 非自身免疫性疾病，希望包围的网站， 缺损同样，在自身免疫性糖尿病中， 同一β细胞“装置”的组成部分是免疫学的靶点。 攻击将受到考验。葡萄糖转运蛋白（GT）和 葡萄糖激酶（GK）作为葡萄糖传感“装置”的组成部分， 通过分析这两种基因的表达模式来确定 葡萄糖应答和无应答β细胞系中的蛋白质。在 在假定的葡萄糖传感器中的更远侧部位， 葡萄糖通过升高β细胞中的丙二酰辅酶A， 将脂肪酸从氧化转移到二酰基甘油池中， 增加蛋白激酶C活性;如果是这样，这可能构成可能的 非自身免疫性糖尿病的缺陷位点。胰淀素的作用 非自身免疫性糖尿病的胰岛素反应缺陷也将 仔细检查。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 从巨噬细胞中释放出来免疫机制 对β细胞的破坏将在抗体的研究中得到解决 T细胞直接作用于β细胞抗原， 将分析由HLA分子确定的对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.