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

描述(由申请人提供)：这项资助的总体目标是利用遗传学来确定NOD小鼠中胰岛素依赖型糖尿病(1型糖尿病，T1D)的免疫病理机制。我们最后一次更新这项资助的目的是描述自身反应性T细胞可能下调的自然机制，并了解为什么这些机制在NOD小鼠身上失败。建议使用基因靶向NOD库来研究表达在NOD CD4和CD8 T细胞表面的ADP核糖基转移酶是否在下调自身免疫T效应器方面发挥作用。还概述了利用特定细胞表面归巢分子(整合素)基因工程突变的NOD小鼠的可获得性的研究。这些整合素(L-选择素和β7)的组合对于肠道相关淋巴组织(GALT)的正常定植是必要的。β7整合素是T效应细胞定位于胰腺并介导胰岛β细胞自身免疫性破坏所必需的。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的糖尿病催化剂之间的相互作用，这是激活这些糖尿病T效应器所必需的。本实验旨在阐明口服胰岛素抑制NOD小鼠糖尿病的机制。鉴于正在进行的NIDDK试验旨在通过口服胰岛素治疗预防被认为是高危人群的T1D，这些后一项研究尤其重要。

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.