Genetics and Pathology of Non-Obese Diabetic (NOD) Mice

描述（由申请人提供）：本资助的总体目标是利用遗传学来确定NOD小鼠胰岛素依赖型糖尿病（1型糖尿病，T1D）的免疫发病机制。我们的最终目标是描述自身反应性T细胞可能下调的自然机制，并了解这些机制在NOD小鼠中失败的原因。利用基因靶向NOD储存库研究在NOD CD4+和CD8+ T细胞表面表达的酶adp -核糖基转移酶是否在下调自身免疫T效应物中发挥作用。还概述了利用在特定细胞表面归巢分子（整合素）中具有基因工程突变的NOD小鼠库存的研究。这些整合素（l -选择素和β 7）的组合对于肠道相关淋巴组织（GALT）的正常定植是必要的。Beta7整合素是t效应细胞返回胰腺和介导胰腺细胞自身免疫破坏所必需的。这些独特的库存将允许分析肠道相关淋巴组织和天然成分饮食中激活这些致糖尿病t效应物所需的致糖尿病催化剂之间的相互作用。本实验旨在阐明口服胰岛素对NOD小鼠糖尿病抑制作用的机制。鉴于正在进行的通过口服胰岛素治疗预防高风险人群T1D的NIDDK试验，后一项调查尤为重要。

DESCRIPTION (provided by applicant): The overall objective of this grant is to use genetics to define mechanisms underlying immunopathogenesis of insulin dependent diabetes mellitus (Type 1 Diabetes, T1D) in the NOD mouse. Our objective in this final renewal of the grant is to delineate the natural mechanisms whereby autoreactive T cells may be downregulated and understand why these mechanisms fail in the NOD mouse. Studies using gene targeted NOD stocks are proposed to investigate whether ADP-ribosyltransferases, enzymes expressed on the surface of NOD CD4+ and CD8+ T cells, play a role in down-regulating autoimmune T-effectors. Studies are also outlined which take advantage of the availability of stocks of NOD mice with genetically engineered mutations in specific cell surface homing molecules (integrins). Combinations of these integrins (L-selectin and Beta7) are necessary for normal colonization of the gut associated lymphoid tissue (GALT). The Beta7 integrin is required for T-effector cells to home to the pancreas and mediate autoimmune destruction of the pancreatic beta cells. These unique stocks will permit analysis of the interaction between the gut associated lymphoid tissue and diabetogenic catalysts in natural ingredient diet required to activate these diabetogenic T-effectors. Experiments are proposed to elucidate the mechanism of diabetes suppression in NOD mice by oral insulin administration. These latter investigations are of particular importance in view of an ongoing NIDDK trial to prevent T1D in humans deemed at high risk by oral insulin treatment.