Mitochondrial Diabetes & Manganic Porphyrin Treatment

描述(由申请人提供)： 自从我们初步证明线粒体DNA(MtDNA)突变可导致II型糖尿病以来，已有大量证据支持这一假说，即II型糖尿病是遗传性部分线粒体氧化磷酸化(OXPHOS)缺陷的产物，该缺陷抑制了线粒体热量的代谢，增加了线粒体活性氧(ROS)的产生。ROS形成的氧化应激进一步侵蚀靶组织和胰腺细胞的线粒体功能，导致胰岛素抵抗、胰岛素分泌丧失和细胞凋亡。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家系中鉴定导致糖尿病的遗传性线粒体DNA突变。然后，我们将使用线粒体转移技术将这些突变置于肝和胰腺细胞的核背景上，然后为这些线粒体DNA突变相关的生化缺陷鉴定这些线粒体细胞系。然后用金属卟啉超氧化物歧化酶(SOD)模拟物处理这些相同的细胞系，以确定用这些催化抗氧化剂可以减少和改善mtDNA突变引起的生化缺陷。此外，我们将研究线粒体抗氧化防御(Sod2)和OXPHOS ATP产生(ANT1和Ant2)存在遗传缺陷的小鼠，以将糖尿病的发展与与年龄相关的线粒体功能下降和胰岛素靶组织和胰岛素分泌组织中体细胞mtDNA突变的积累联系起来。这些小鼠还将接受金属卟啉模拟物的治疗，以确定这些药物是否会延缓症状的发展和体细胞mtDNA突变的积累。

DESCRIPTION (provided by applicant): 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 inhibits the 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 ¿ cells, leading to insulin resistance, loss of insulin secretion, and ¿ 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 characterize these cybrid cell lines for the biochemical defects associated 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 (Ant1 and 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 metalloporphyrin mimetics to determine if these drugs will then delay the development of the symptoms and the accumulation of the somatic mtDNA mutations.