GENETICS AND PATHOLOGY OF NON-OBESE DIABETES

该应用程序代表了一个跨学科的努力，以表征 非肥胖型糖尿病（NOD）患者糖尿病综合征的病因病理基础 小鼠 这些老鼠自发地发展出一种糖尿病综合症， 人类自身免疫相关的I型糖尿病。 的性质和 NOD小鼠中糖尿病发生的潜在基因的数量将通过以下方法分析： 与糖尿病易感近交系遗传背景的异交。 主要组织相容性复合体基因和 将评估内源性β细胞逆转录病毒。 的 糖尿病性二态性表现的病理生理基础 在NOD小鼠中（雌性发生率为75%，雄性为29%）， 通过结合内分泌和免疫学比较， 男性和女性。 由于胰岛炎和自身抗体的产生 对胰岛的作用是胰腺炎的显著病理指标， NOD小鼠处于糖尿病前期状态，其免疫功能将 仔细比较糖尿病抵抗的非肥胖正常（NON） 亚株 自身免疫、胰岛自身抗原和 将探索β细胞的破坏。 肿瘤相关组织病理学 将确定其他组织和器官的变化。 拟议 使用免疫系统操作的研究应该允许 了解免疫调节缺陷是如何在糖尿病易感人群中 基因型可引发导致显性糖尿病的发病后遗症。

This application represents an interdisciplinary effort to characterize the etiopathologic bases of the diabetes syndrome in non-obese diabetic (NOD) mice. These mice spontaneously develop a diabetes syndrome resembling autoimmune-associated type I diabetes mellitus in humans. The nature and number of genes underlying diabetogenesis in NOD mice will be analyzed by outcrosses onto diabetes-susceptible inbred strain genetic backgrounds. The pathogenic significance of major histocompatibility complex genes and of endogenous beta cell retroviruses will be assessed. The physiopathological basis for the sexually dimorphic expression of diabetes in NOD mice (75% incidence in female versus 29% in males) will be established by a combined endocrinologic and immunologic comparison of males and females. Since insulitis and production of autoantibodies against pancreatic islets are the salient pathologic indicators of the pre-diabetic state in NOD mice, their immunologic functions will be carefully compared to the diabetes-resistant non-obese normal (NON) substrain. The relationship between autoimmunity, islet autoantigens, and beta cell destruction will be explored. Age-associated histopathological changes in other tissues and organs will be established. The proposed studies employing manipulation of the immune system should allow an understanding of how defects in immunoregulation in a diabetes-susceptible genotype can trigger pathogenetic sequelae leading to overt diabetes.