mt-Nd2 and Resistance to Autoimmune Diabetes

描述：线粒体（mt）在细胞能量产生和细胞死亡中起关键作用。β细胞功能与线粒体紧密相关，因为胰岛素合成和葡萄糖刺激的胰岛素分泌都需要线粒体ATP产生。在这种情况下，与人类2型糖尿病（T2 D）家系相关的线粒体DNA（mtDNA）突变的报告占人类T2 D的1%。线粒体DNA突变通常与自身免疫性1型糖尿病（T1 D）无关，尽管在高危人群和T1 D易感NOD与T1 D耐药ALR小鼠的杂交中，导致mt-ND 2基因中亮氨酸取代为蛋氨酸的C至A颠换与T1 D保护相关。本申请的目的是了解这种单一氨基酸变化如何预防T1 D。T1 D易感性的遗传分析将注意力集中在控制异常免疫细胞功能的候选基因上，而很少关注可能在B细胞水平上贡献易感性或抗性的基因。来自ALR小鼠品系的胰岛对自身免疫效应物的功能损伤和杀伤保持不寻常的遗传抗性。初步结果已经将这种升高的ft细胞抗性中的一些与ALR的mt-Nd 2等位基因联系起来。我们的目标是了解该基因在B细胞抵抗自身免疫性杀伤中的作用。第一个目的是确定ALR的mt-Nd 2等位基因提供的自发性T1 D的保护程度，然后使用特定细胞群的过继转移实验详细说明这种抗性。在第二个目标中，mt-Nd 2等位基因对mt功能的影响将通过研究孤立的mt来检查。还将测试mt以确定当用自由基或凋亡刺激物应激时，ALR的mt-Nd 2a等位基因是否提供mt的功能增益。由于T1 D耐药人群和ALR小鼠中的SNP及其伴随的氨基酸变化相似，因此从本申请中获得的信息可能会直接影响未来预防或治愈T1 D的工作。

Description: Mitochondria (mt) play key roles in cellular energy production and cell death. Beta cell function is tightly linked to mitochondria, as both insulin synthesis and glucose stimulated insulin secretion require mitochondrial ATP production. In this context, reports of mitochondrial DNA (mtDNA) mutations associated with Type 2 diabetes (T2D) pedigrees in humans account for up to 1% of human T2D. Mutations in mtDNA are not commonly associated with autoimmune Type 1 diabetes (T1D), although a C to A transversion resulting in a leucine to methonine substitution in the mt-ND2 gene has been associated with protection from T1D in both an at risk human population and in crosses of the T1D-prone NOD with T1D-resistant ALR mice. The goal of this application is to understand how this single amino acid change can protect against T1D. Genetic analysis of T1D susceptibility has focused attention on candidate genes controlling aberrant immune cell function with little focus on genes that may contribute susceptibility or resistance at the B cell level. Pancreatic islets from the ALR mouse strain maintain an unusual genetic resistance to functional impairment and killing by autoimmune effectors. Preliminary results have linked some of this heightened ft cell resistance to the mt-Nd2 allele of ALR. Our goal is to understand the role this gene plays in B cell resistance to autoimmune killing. The first aim is to determine the extent of protection from spontaneous T1D provided by ALR's mt-Nd2 allele, and then detail this resistance using adoptive transfer experiments with specific cell populations. In the second aim the impact of the mt-Nd2 allele on mt function will be examined by studying isolated mt. The mt will also be tested to determine if ALR's mt-Nd2a allele provides a gain of function to mt when stressed with free radicals or apoptotic stimuli. As the SNP and its accompanying amino acid change in the T1D resistant human population and ALR mouse are similar, it is likely that the information gleened from this application can directly impact future work to prevent or cure T1D.