Mitochrondrial Dysfunction: Role in Metabolic Syndrome

该计划的目标是了解线粒体功能障碍对胰岛素抵抗和其他相关代谢紊乱的作用。该计划涉及多个部门成员之间的协作互动，并组织成三个项目，由三个核心设施支持。在临床生理学，生物化学，人类遗传学，细胞和分子生物学和核磁共振光谱（MRS）领域的专业知识将集中在线粒体功能障碍在人类疾病中的作用。我们将讨论以下问题：（1）线粒体功能障碍是否是2型糖尿病父母的年轻瘦型血糖正常后代的肌肉/肝脏脂肪蓄积和胰岛素抵抗的原因（IR后代），（2）哪些基因负责降低线粒体活性/IR后代和高血压及高脂血症家族中的高脂蛋白含量，这似乎是由于线粒体中的一种新的同质突变。tRNA/ile. (3)在这些患者以及胰岛素抵抗的老年受试者中，脑线粒体代谢是否受到影响？这些问题将通过这3个项目的主要研究者之间的合作互动来解决，具体如下：（项目1）-Shulman博士将解决线粒体功能障碍在IR后代胰岛素抵抗发病机制中的作用。该项目建立在他的小组的初步数据基础上，这些数据表明这些个体的肌细胞内脂质含量增加，这可归因于线粒体活性降低。该项目将进一步探索这些个体的肝脏和肌肉中的线粒体功能，使用13 C/31 p/1H MRS结合通过细胞和分子方法直接检查肌肉组织，使用新的LC/MSIMS方法直接定量线粒体含量，胰岛素信号传导和蛋白磷酸化，（项目2）-利夫顿博士将检查从IR后代和胰岛素敏感对照受试者中获得的肌肉活检样本中的核和线粒体DNA，这些受试者已经被 在项目#1中进行了表征，以鉴定负责降低的线粒体功能/含量和胰岛素抗性的基因。本项目将检验调节线粒体生物发生的基因的改变是胰岛素抵抗的原因这一假设。该项目还将进一步描述高血压和高脂血症患者的特征，他的小组的初步数据表明，高血压和高脂血症是由线粒体tRNA/ ile中的新型同质突变引起的。（项目3）-博士，罗斯曼将采用新的C/31 P MRS技术来检查脑线粒体功能：1）最近被证明由于线粒体功能障碍而具有胰岛素抵抗的健康老年志愿者，2）在项目2中鉴定的具有与高血压和血脂不足相关的新型线粒体tRNA/ ile突变的患者，和3）在项目1中鉴定的患有2型糖尿病的父母的胰岛素抵抗后代。这三个项目将由一个行政核心（核心A）、一个临床核心（核心B）和一个MRS/MRI核心（核心C）提供支持，行政核心（核心A）负责协调整个项目。该计划是由该计划的教师和研究工作者bdnging这些不同的方法，以解决一个共同的目标经常会议协调。

The goal of this program is understand the role of mitochondrial dysfunction on insulin resistance and other related metabolic disorders in humans. The program involves collaborative interactions between members of several departments, and is organized into three projects supported by three core facilities. Expertise in the fields of clinical physiology, biochemistry, human genetics, cell & molecular biology and nuclear magnetic resonance spectroscopy (MRS) will focus on the role of mitochondrial dysfunction in human disease. We will address the following questions: (1) Is mitochondrial dysfunction responsible for fat accumulation in muscle/liver and insulin resistance in young lean normorglycemic offspring of parents with type 2 diabetes (IR offspring), (2) What genes are responsible for reduced mitochondrial activity/content in IR offspring and families with hypertension and hyperlipidemia which appears to be due to a novel homoplasmic mutation in a mitochondrial tRNA/ile. (3) is brain mitochonddal metabolism affected in these patients as well as in insulin resistant elderly subjects? These questions will be addressed by collaborative interactions between the Principal Investigators of these 3 projects, which are as follows: (Project 1) - Dr. Shulman will address the role of mitochondrial dysfunction in the pathogenesis of insulin resistance in IR offspring. This project builds on preliminary data by his group demonstrating that these individuals have increased intramyocellular lipid content, which can be attributed to reduced mitochondrial activity. This project will further explore mitochondrial function in liver and muscle of these individuals using 13C/31p/1H MRS in combination with direct examination of muscle tissue by cellular and molecular approaches to directly quantify mitochondrial content, insulin signaling and protein phosphorylation using a novel LC/MSIMS approach, (Project 2) - Dr. Lifton will examine nuclear and mitochondrial DNA in muscle biopsy samples obtained from IR offspring and insulin sensitive control subjects that have been characterized in Project #1 in order to identify genes responsible for reduced mitochondrial function/content and insulin resistance. This project will examine the hypothesis that alterations in genes regulating mitochonddal biogenesis are responsible for insulin resistance. This project will also further characterize patients with hypertension and hyperlipidemia which preliminary data by his group suggests is caused by a novel homoplasmic mutation in a mitochondrial tRNA/ ile. (Project 3) - Dr, Rothman will employ novel C/31P MRS techniques to examine brain mitochondrial function in: 1) healthy elderly volunteers who have recently been shown to be insulin resistant due to mitochondrial dysfunction, 2) patients with the novel mitochondrial tRNA/ ile mutation associated with hypertension and hypedipidemia identified in Project 2, and 3) insulin resistant offspring of parents with type 2 diabetes identified in Project 1. These three projects will be supported by an Administrative Core (Core A) to coordinate the project as a whole, a Clinical Core (Core B) and a MRS/MRI Core (Core C). The program is coordinated by frequent meetings of the program faculty and research workers bdnging together these diverse approaches to address a common goal.