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Mitochondrial Diabetes & Manganic Porphyrin Treatment

线粒体糖尿病

基本信息

批准号：
8007475
负责人：
Douglas C Wallace
金额：
$ 10万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-31 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8007475
关键词：
Animals Antioxidants Apoptosis Biochemical Calories Cell Death Cell Line Cells Chronic Clinical Defect Development Diabetes Mellitus Disease Electron Transport Electrons Etiology Family Fatty acid glycerol esters Functional disorder Gene Expression Glucose Hepatic Human Inherited Insulin Insulin Resistance Link Liver Metabolism Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitotic Molecular Mus Mutation Nature Nephrons Neurons Non-Insulin-Dependent Diabetes Mellitus Nuclear Oxidative Phosphorylation Oxidative Phosphorylation Deficiency Oxidative Stress Pancreas Peripheral Pharmaceutical Preparations Porphyrins Production Reactive Oxygen Species Research Design Research Personnel Retinal Role Superoxide Dismutase Symptoms Techniques Testing Tissues Toxic effect Vascular Endothelial Cell age related base diabetic diabetic patient genetic pedigree insulin secretion mimetics mitochondrial DNA mutation mitochondrial permeability transition pore mouse model nonalcoholic steatohepatitis oxidative damage programs

项目摘要

Since our initial demonstration that mitochondrial DNA (mtDNA) mutations can result in Type II diabetes, considerable evidence has accumulated supporting the hypothesis that Type II diabetes is the product of inherited partial mitochondrial oxidative phosphorylation (OXPHOS) deficiency which inhibitsthe mitochondrial metabolism of calories and increases mitochondrial production of reactive oxygen species (ROS). The oxidative stress form the ROS further erodes mitochondrial function in both target tissues and in pancreatic p cells, leading to insulin resistance, loss of insulin secretion, and (3 cells apoptosis. To further clarify the role of mtDNA mutations in Type II diabetes, we propose to identify the inherited mtDNA mutations causing diabetes in a number of maternally inherited diabetes pedigrees. We will then use the cybrid transfer technique to place these mutations onto hepatic and pancreatic cell nuclear backgrounds and then the characterize these cybrid cell lines for the biochemical defects assoiated with the mtDNA mutations. These same cell lines with then be treated with metallopophyrin superoxide dismutase (SOD) mimetics to determine with these catalytic antioxidants can reduce ameliorate the biochemical defect caused by the mtDNA mutation. In addition, we will study mice with inherited defects in mitochondrial antioxidant defenses (Sod2) and in OXPHOS ATP production (Antl & Ant2) to correlate the development of diabetes with the age-related decline in mitochondrial function and the accumulation of somatic mtDNA mutations in both insulin target and insulin secreting tissues. These mice will also be treated with the metalloporphyrinmimetics to determine if these drugs will then delay the development of the symptoms and the accumulation of the somatic mtDNA mutations.

自从我们最初证明线粒体DNA(MtDNA)突变会导致II型糖尿病以来，相当大的越来越多的证据支持这一假设，即II型糖尿病是遗传性部分糖尿病的产物。线粒体氧化磷酸化(OXPHOS)缺乏抑制线粒体代谢卡路里和增加线粒体产生的活性氧(ROS)。ROS形成的氧化应激进一步侵蚀靶组织和胰腺p细胞的线粒体功能，导致胰岛素抵抗、丧失。胰岛素分泌减少，(3)细胞凋亡。为了进一步阐明线粒体DNA突变在II型糖尿病中的作用，我们建议在一些母系遗传性糖尿病中确定导致糖尿病的遗传性mtDNA突变血统。然后，我们将使用半胱氨酸转移技术将这些突变放置在肝脏和胰腺细胞上。核背景，然后表征这些胞质细胞系的生化缺陷与线粒体DNA突变。然后用金属卟啉超氧化物歧化酶(SOD)处理这些细胞系。模拟测定这些具有催化作用的抗氧化剂可以减少和改善由线粒体DNA突变。此外，我们还将研究线粒体抗氧化防御遗传缺陷的小鼠(Sod2)。以及在OXPHOS ATP产生(ANT1和ANT2)中，将糖尿病的发展与年龄相关的胰岛素靶向和胰岛素分泌中线粒体功能和体细胞mtDNA突变的积累纸巾。这些小鼠还将接受金属卟啉类药物的治疗，以确定这些药物是否会推迟症状的发展和体细胞线粒体DNA突变的积累。