GENETICS AND PATHOLOGY OF NON-OBESE DIABETES

这个应用程序代表了跨学科的努力，以表征 非肥胖型糖尿病(NOD)合并糖尿病综合征的病因病理基础 老鼠。这些小鼠自发地发展成一种类似于 人类自身免疫相关性I型糖尿病。自然界和 NOD小鼠糖尿病发生的潜在基因的数量将通过 与易患糖尿病的近交系遗传背景杂交。 主要组织相容性复合体基因及其致病意义 将对内源性β细胞逆转录病毒进行评估。这个 糖尿病性二型性表现的生理病理基础 在NOD小鼠(雌性发病率为75%，雄性为29%)中， 通过内分泌学和免疫学的联合比较来确定 雄性和雌性。由于胰岛炎症和自身抗体的产生 抗胰岛是该病的显著病理指标。 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者(Non) 亚株。自身免疫、胰岛自身抗原与 将探索对β细胞的破坏。年龄相关组织病理学 其他组织和器官的变化将得到证实。建议数 利用对免疫系统的操纵的研究应该允许 对糖尿病易感人群免疫调节缺陷的理解 基因分型可引发病理性后遗症，导致明显的糖尿病。

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.