Pathophysiology /genetics of diabetes mellitus model

糖尿病模型的病理生理学/遗传学

• 批准号: 6576250
• 负责人: SIGURD LENZEN
• 金额: $ 25万
• 依托单位: HANNOVER MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6576250
• 关键词: MHC class II antigen; apoptosis; autoimmunity; cell population study; diabetes mellitus genetics; disease /disorder model; gene mutation; genetic mapping; genetic models; histopathology; immunocytochemistry; insulin dependent diabetes mellitus; laboratory rat; model design /development; pancreatic islets; pathologic process; pathology; physiology; terminal nick end labeling

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.

描述（由申请人提供）： 具有自发发展的胰岛素依赖型糖尿病的啮齿动物模型具有人类1型糖尿病（T1 DM）的许多典型特征，并且在鉴定自身免疫性糖尿病的病因学和病理生理学方面非常有帮助。LEW.1AR1/Ztm-iddm大鼠是一种新的T1 DM动物模型。它是通过一种具有确定的MHC单倍型（RTI. A a B/Du Cu）的同系刘易斯大鼠品系的自发突变而产生的。这种新模型具有重要意义，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，以便这种新的菌株可以很好地用于世界范围内的实验性糖尿病研究。特别是病理生理学、自身免疫和遗传学方面的信息已被科学界所要求。因此，我们的目标是在本项目中表征新的LEW.1AR1/Ztm-iddm大鼠，使其能够作为定义的T1 DM动物模型提供给国际科学界，作为现有T1 DM动物模型的补充。应实现以下三个主要目标：A.自身免疫过程的表征，以分析糖尿病前期期间自身免疫过程的时间进程，包括β细胞破坏和胰岛浸润的凋亡过程的启动，最终导致明显的糖尿病状态的表现。B。通过过继转移证明糖尿病综合征的自身免疫性质，通过对选定T细胞亚群的详细过继转移研究，证明该新动物模型中糖尿病综合征的自身免疫性质。C.分析导致胰岛素依赖型糖尿病的遗传基因座，以鉴定可能与表达突变而非“标准”u-单倍型的MHC II类区域相关的基因座，或与与主要组织相容性复合体（MHC）无关的突变的免疫活性调节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鉴定β细胞破坏的遗传学和发病机制的关键要素，将为开发预防和治愈人类T1 DM的新治疗策略提供基础。本申请中提出的表征将允许全球科学界为此目的适当使用这种新的T1 DM大鼠模型。