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：
8475461
负责人：
CLAYTON E MATHEWS
金额：
$ 30.33万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8475461
关键词：
ALR Mouse Accounting Alleles Alloxan Amino Acids Antigen Targeting Apoptotic Attention Autoimmune Diabetes Autoimmune Process Beta Cell Biological Assay Blood Pressure Breeding CD8-Positive T-Lymphocytes CD8B1 gene Candidate Disease Gene Cell Death Cell Death Signaling Process Cell Line Cell Nucleus Cell physiology Cell-Mediated Cytolysis Cells Cessation of life Collection Communication Complex Cytochrome c Reductase Cytolysis Cytotoxic T-Lymphocytes Data Development Diabetes Mellitus Engraftment Figs - dietary Future Generations Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genomics Glucose Goals Granzyme Human Human Characteristics Immune Immune system In Vitro Inbred NOD Mice Individual Injury Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Knowledge Lead Leucine Life Ligation Link Longevity Mediating Membrane Potentials Metabolism Mitochondria Mitochondrial DNA Mouse Strains Mus Mutation Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Nuclear Oxidative Stress Pancreas Pathogenesis Pathology Pathway interactions Patients Play Population Predisposition Production Protocols documentation Reactive Oxygen Species Reporting Research Research Design Resistance Risk Role Signal Transduction Single Nucleotide Polymorphism Source Stress T-Lymphocyte TNF gene TNFRSF1A gene Testing Tissues Transplantation Tumor Necrosis Factor Receptor Variant Visual Work atherogenesis attenuation cellular engineering cohort cytokine free radical oxygen functional disability genetic analysis genetic element genetic pedigree genetic variant glucose tolerance improved insight insulin secretion islet killings member mitochondrial DNA mutation mouse model perforin prevent receptor resistance mechanism stem therapeutic target ward

项目摘要

DESCRIPTION (provided by applicant): 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 diabetes (T2D) pedigrees in humans account for up to 1% of human T2D. However, 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 modifies resistance to 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 ¿ cell level. Pancreatic islets from the ALR mouse strain maintain an unusual genetic resistance to functional impairment and killing by autoimmune effectors. Our results have linked some of the ALR-derived T1D resistance to mt- Nd2a. While this allele does not prevent the development of spontaneous T1D when introgressed into the NOD genetic background, the ALR-derived genetic variant does in fact protect beta cells from destruction by cytotoxic T lymphocytes as well as combined cytokines. We have determined that this resistance stems from the inability of pro-apoptotic stress to induce mt reactive oxygen species. Our goal is to understand the role this gene plays in ¿ cell resistance to autoimmune killing. In specific aim 1 we will determine the mechanism by which mt-Nd2a encoding ¿ cells and primary islets resist destruction mediated by members of the Tumor Necrosis Factor Receptor family, TNFR1 and Fas. Aim 2 will extend the studies to determine the mechanisms utilized by mt-Nd2a encoding islet cells to avert lysis by CTL. Specific aim 3 will use human islets to confirm mechanisms of resistance to ¿ cell destruction as well as cybrid human ¿ cells to test if the human alleles of mt-ND2 alter the characteristics of human ¿ cell death. The studies, as proposed, will provide meaningful data on both the early apoptotic signals that result in human beta cell death as well as insights into how ND2a protects human beta cells.

描述（由适用提供）：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。由于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，人类中与糖尿病（T2D）血统有关的线粒体DNA（mtDNA）突变的报告最多占人类T2D的1％。然而，mtDNA中的突变通常与自身免疫性1型糖尿病（T1D）无关，尽管A c to tress to t tertrose的c导致MT-ND2基因中的亮氨酸替代亮氨酸与t1d人群中的T1D均与T1D cross and T1d-prone nod nod Nod contert and a t1d-nod Nod a a t1d-al a al a al a al a al a al a al a al a al a al a al a ail mice均与T1D的保护有关。该应用的目的是了解这种单个氨基酸改变修饰符对T1D的抗性。 T1D敏感性的遗传分析将注意力集中在控制异常免疫核管功能的候选基因上，而几乎没有关注可能在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杀死的异常遗传抗性。我们的结果已将ALR衍生的T1D抗性与MT-ND2A联系起来。尽管该等位基因并不能阻止在浸入点头遗传背景时发育T1D的发展，但实际上，ALR衍生的遗传变异确实可以保护β细胞免受细胞毒性T淋巴细胞以及结合细胞因子的破坏。我们已经确定，这种抗性阶段源于促凋亡应激无法诱导MT活性氧。我们的目标是了解该基因在自身免疫性杀死的细胞耐药性中的作用。在特定目标1中，我们将确定 MT-ND2A编码细胞和原代胰岛抵抗由肿瘤坏死因子受体家族TNFR1和FAS介导的破坏的机制。 AIM 2将扩展研究，以确定MT-ND2A编码胰岛细胞使用的机制，以避免CTL裂解。具体目标3将使用人类胰岛来确认对细胞破坏的抗性机制以及cybrid人»细胞，以测试MT-ND2的人类等位基因是否改变了人类细胞死亡的特征。据提出，这些研究将提供有意义的数据，这些数据对早期的凋亡信号，这些信号导致人β细胞死亡以及对ND2A如何保护人β细胞的见解。