mt-Nd2 and Resistance to Autoimmune Diabetes

mt-Nd2 与自身免疫性糖尿病的抵抗力

基本信息

批准号：
7998873
负责人：
CLAYTON E MATHEWS
金额：
$ 11.31万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-15 至 2010-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7998873
关键词：
Accounting Address Adoptive Transfer Alleles Alloxan Amino Acids Animal Model Apoptotic Attention Autoimmune Diabetes Autoimmune Process B-Lymphocytes Beta Cell Breeding Candidate Disease Gene Cell Death Cell Nucleus Cell physiology Cells Cessation of life Communication Complex Cytochrome c Reductase Diabetes Mellitus Free Radicals Future Generations Genes Genetic Glucose Goals Human Immune Injury Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Laboratories Leucine Life Link Major Histocompatibility Complex Mediating Metabolism Mitochondria Mitochondrial DNA Mouse Strains Mus Mutation Non-Insulin-Dependent Diabetes Mellitus Nuclear Pancreas Play Population Predisposition Production Reporting Research Design Resistance Risk Role Single Nucleotide Polymorphism Source Stimulus Stress T-Lymphocyte Testing Variant Work cohort cytokine free radical oxygen functional disability gain of function genetic analysis genetic pedigree insulin secretion islet killings mitochondrial DNA mutation prevent progenitor research study

项目摘要

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.

描述：线粒体（MT）在细胞能量生产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，人类中与2型糖尿病（T2D）血统相关的线粒体DNA（mtDNA）突变的报告最多占人类T2D的1％。 mtDNA中的突变通常与自身免疫1型糖尿病（T1D）无关，尽管在MT-ND2基因中导致亮氨酸替代的c to tresstrestion c to thee c c均与t1d的甲烷取代有关在用T1D抗ALR小鼠的T1D易发点头。该应用程序的目的是了解这种单个氨基酸变化如何防止T1D。 T1D易感性的遗传分析将注意力集中在控制异常的免疫细胞功能的候选基因上，而很少关注可能在B细胞水平上有助于敏感性或抗性的基因。 ALR小鼠菌株的胰岛保持了对功能障碍和自身免疫性效应子杀死的异常遗传抗性。初步结果将这种增强的FT细胞耐药性与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细胞抗自身免疫性杀伤中的作用。第一个目的是确定ALR MT-ND2等位基因提供的自发T1D的保护程度，然后使用具有特定细胞群体的收养转移实验详细介绍了这种阻力。在第二个目标中，MT-ND2等位基因对MT功能的影响将通过研究分离的MT来检查。还将对MT进行测试，以确定ALR的MT-ND2A等位基因在用自由基或凋亡刺激压力时是否为MT提供了功能。由于SNP及其伴随的T1D抗抗体人群和ALR小鼠的氨基酸变化相似，因此从本应用中获取的信息可能会直接影响未来的工作以防止或治愈T1D。