MITOCHONDRIA AND METABOLIC SYNDROME IN A SOUTHERN CALIFORNIA CHINESE COHORT

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 自从13年前我们的实验室首次将2型糖尿病与一个三代母系的线粒体DNA重排联系起来以来，越来越多的人支持我们的假设，即线粒体功能障碍在2型糖尿病(DM)和重叠代谢综合征(MS)的病因中起着重要作用。通过这项研究，我们计划通过对线粒体DNA(MtDNA)中有害序列变异可能导致的线粒体氧化磷酸化(OXPHOS)缺陷的广泛调查，大大扩展该领域的现有知识。这些导致糖尿病的mtDNA变异被认为范围从最近的相对严重的突变导致家族性DM&MS的大量OXPHOS缺陷到古老的相对轻微的多态导致部分OXPHOS缺陷并增加患DM&MS的风险。 为了验证这一假设，我们建议分析现有的台湾中国家庭样本的mtDNA，这些样本显示DM和MS的母系传播，以及大约500名台湾中国人非家族性DM/MS病例和对照的mtDNA突变，以确定致病原因。这项研究旨在寻找共同的亚洲线粒体DNA谱系(单倍群)与多发性硬化症和糖尿病易感性之间的联系。台湾样本队列将不包括在此IRB申请中，但将属于已提交给调查审查委员会的另一份豁免地位申请。(已递交申请11/01/05)。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Since our laboratory's initial linkage of Type 2 diabetes to a mtDNA rearrangement in a three generation maternal pedigree 13 years ago, there has been increasing support for our hypothesis that mitochondrial dysfunction plays an important role in the etiology of Type 2 Diabetes Mellitus (DM) and the overlapping Metabolic Syndrome (MS). With this study we are planning to substantially expand upon the existing knowledge in the field by an extensive investigation of defects in mitochondrial oxidative phosphorylation (OXPHOS) caused potentially by deleterious sequence variants in the mitochondrial DNA (mtDNA). These diabetogenic mtDNA variants are proposed to range from recent, relatively severe, mutations resulting in substantial OXPHOS defects with familial DM & MS to ancient, relatively mild, polymorphisms that result in partial OXPHOS defects and an increase in the risk to develop DM & MS. To test this hypothesis, we propose to analyze the mtDNAs of an existing collection of samples from Taiwan Chinese families, which exhibit maternal transmission of DM & MS as well as approximately 500 Taiwan Chinese DM/MS non familial cases and controls to identify causal pathogenic mtDNA mutations. The study is designed to look for associations between the common Asian mtDNA lineages (haplogroups) and predisposition to MS and DM. The Taiwanese cohort of samples will not be included under this IRB application but will fall under a separate, exempt status application which has been submitted to the Investigational Review Board. (application submitted 11/01/05).