Pathophysiology /genetics of diabetes mellitus model

描述(由申请人提供)： 自发发展成胰岛素依赖型糖尿病的啮齿动物模型具有许多人类1型糖尿病(T1 DM)的典型特征，对于识别自身免疫性糖尿病的病因和病理生理方面具有极大的帮助。LEW.1AR1/ZTM-IDDM大鼠是一种新的T1 DM动物模型。它是通过一个同源的Lewis大鼠品系的自发突变而产生的，该品系具有特定的MHC单倍型(RTI.A，B/Du，Cu)。这一新模型引起了人们的极大兴趣，因为它似乎与人类疾病非常相似。特别是，这种新的大鼠模型没有显示出免疫系统的遗传缺陷。然而，详细的知识是必不可少的，这样这种新的菌株才能很好地应用于世界各地的实验性糖尿病研究。科学界特别要求提供有关病理生理学、自身免疫和遗传学的信息。因此，我们的目标是在本项目中对新的LEW.1AR1/ZTM-IDDM大鼠进行表征，以使其能够作为一种明确的T1 DM动物模型提供给国际科学界，补充现有的T1 DM动物模型。应达到以下三个主要目标：a.自身免疫过程的特征，以分析糖尿病前期的自身免疫过程的时间进程，包括启动β细胞破坏和胰岛浸润的凋亡过程，最终导致明显的糖尿病状态的表现。B.通过过继移植证明糖尿病综合征的自身免疫性通过对选定的T细胞亚群进行详细的过继移植研究，在这一新的动物模型中证明糖尿病综合征的自身免疫性。C.分析导致胰岛素依赖型糖尿病的遗传基因座，以确定可能与表达突变的而不是标准的U-单倍型的MHC II类区域相关的基因座，或者与主要组织相容性复合体(MHC)无关的免疫活性突变调控基因座相关的基因座。在这种新的自身免疫性糖尿病动物模型中识别β细胞破坏的遗传学和发病机制的关键因素将为开发新的治疗策略来预防和治疗人类T1 DM提供基础。本申请中提出的特征将允许世界各地的科学界为此目的正确使用这种新的T1 DM大鼠模型。

DESCRIPTION (provided by applicant): Rodent models with spontaneous development of insulin-dependent diabetes mellitus share many features typical for human type 1 diabetes mellitus (T1DM) and have been extremely helpful in identifying etiological and pathophysiological aspects of autoimmune diabetes. The LEW.1AR1/Ztm-iddm rat is a new T1DM animal model. It arose through a spontaneous mutation in a congenic Lewis rat strain with a defined MHC haplotype (RTI.A a B/Du Cu ). This new model is of significant interest because it appears to closely parallel the human disease. In particular this new rat model shows no inherited defects of the immune system. However, detailed knowledge is essential so that this new strain can be well utilized in experimental diabetes research world-wide. In particular information on the pathophysiology, the autoimmunity and the genetics has been requested by the scientific community. We therefore aim at characterizing the new LEW.1AR1/Ztm-iddm rat in this project to such an extent that it can be offered as a defined T1DM animal model to the international scientific community complementary to the existing animal models of T1DM. The following three major aims should be addressed: A. Characterization of the autoimmune process to analyze the time course of the autoimmune process during the pre-diabetic phase, both with respect to the initiation of the apoptotic process of beta cell destruction and islet infiltration, ultimately leading to the manifestation of an overt diabetic state. B. Proof of the autoimmune nature of the diabetic syndrome through adoptive transfer to demonstrate the autoimmune nature of the diabetic syndrome in this new animal model through detailed adoptive transfer studies with selected T cell subpopulations. C. Analysis of the genetic locus responsible for the insulin-dependent diabetes mellitus to identify the locus which could be associated either with a MHC class II region expressing a mutated rather than a "standard" u-haplotype, or with a mutated immunologically active regulatory locus unrelated to the major histocompatibility complex (MHC). Identification of the key elements of the genetics and pathogenesis of beta cell destruction in this new animal model of autoimmune diabetes will provide the basis for the development of novel therapeutic strategies for the prevention and cure of T1DM in humans. The characterization as proposed in this application will allow the proper use of this new T1 DM rat model for this purpose by the scientific community world-wide.