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（由申请人提供）：线粒体 (mt) 在细胞能量产生和细胞死亡中发挥关键作用，与线粒体紧密相关；在这种情况下，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。与人类糖尿病 (T2D) 谱系相关的线粒体 DNA (mtDNA) 突变占人类 T2D 的 1%，然而，mtDNA 突变通常与糖尿病 (T2D) 无关。自身免疫性 1 型糖尿病 (T1D)，尽管 C 到 A 的颠换导致 mt-ND2 基因中亮氨酸替换为甲硫氨酸，这与高危人群和易患 T1D 的 NOD 杂交中预防 T1D 的作用有关该应用的目的是了解这种单一氨基酸变化如何改变对 T1D 的抵抗力，对 T1D 易感性的遗传分析将注意力集中在候选基因上。控制异常的免疫细胞功能，很少关注可能导致易感性或抵抗性的基因ALR 小鼠品系的胰岛对功能损伤和自身免疫效应子的杀伤具有异常的抵抗力，我们的研究结果将一些 ALR 衍生的 T1D 抵抗力与 mt-Nd2a 联系起来，但该等位基因并不能阻止其发展。当自发性 T1D 渗入 NOD 遗传背景时，ALR 衍生的遗传变异实际上可以保护 β 细胞免受细胞毒性 T 淋巴细胞以及组合细胞因子的破坏，我们已经确定这种抵抗源于这种抵抗。由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 ¿在具体目标 1 中，我们将确定细胞对自身免疫杀伤的抵抗力。 mt-Nd2a 编码机制 ¿细胞和原代胰岛抵抗肿瘤坏死因子受体家族成员 TNFR1 和 Fas 介导的破坏，目标 2 将扩展研究，以确定编码胰岛细胞的 mt-Nd2a 所利用的机制，以避免 CTL 裂解。人类胰岛以确认抵抗机制 ¿细胞破坏以及细胞杂种人类 ¿细胞来测试 mt-ND2 的人类等位基因是否改变人类的特征 ¿正如所提议的，这些研究将提供有关导致人类 β 细胞死亡的早期细胞凋亡信号的有意义的数据，以及 ND2a 如何保护人类 β 细胞的见解。