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着关键作用。β细胞的功能与线粒体紧密相连，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的产生。在此背景下，报道的与人类2型糖尿病(T2D)家系相关的线粒体DNA(MtDNA)突变占人类T2D的1%。MtDNA突变通常与自身免疫性1型糖尿病(T1D)相关，尽管在高危人群和T1D倾向于NOD与T1D抗性ALR小鼠的杂交中，mt-ND2基因中C到A的转换导致亮氨酸到蛋氨酸的替换与T1D的保护作用有关。这个应用程序的目标是了解这种单一的氨基酸变化如何预防T1D。对T1D易感性的遗传分析主要集中在控制异常免疫细胞功能的候选基因上，而对可能在B细胞水平上导致易感性或耐药性的基因关注较少。来自ALR小鼠品系的胰岛对自身免疫效应器的功能损伤和杀伤保持着不同寻常的遗传抵抗力。初步结果已经将这种增强的ft细胞抵抗力与ALR的mt-nd2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所起的作用。第一个目标是确定ALR的mt-ND2等位基因对自发T1D的保护程度，然后通过对特定细胞群体的过继转移实验来详细说明这种抗性。第二个目的是通过对分离的mt-ND2等位基因的研究，探讨mt-ND2等位基因对mt功能的影响。Mt还将被测试，以确定ALR的mt-Nd2a等位基因在受到自由基或细胞凋亡刺激时是否为mt提供功能增益。由于T1D抗性人群和ALR小鼠的SNP及其伴随的氨基酸变化相似，从这一应用中获得的信息可能会直接影响未来预防或治疗T1D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.