Mitochrondrial Dysfunction: Role in Metabolic Syndrome

该项目的目标是了解线粒体功能障碍在人类胰岛素抵抗和其他相关代谢紊乱中的作用。该计划涉及多个部门成员之间的协作互动，并由三个核心设施支持的三个项目组成。在临床生理学、生物化学、人类遗传学、细胞和分子生物学以及核磁共振波谱(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。我们将解决以下问题：(1)线粒体功能障碍是否会导致2型糖尿病父母(IR子代)年轻瘦削的正常血糖后代(IR子代)肌肉/肝脏中的脂肪积累和胰岛素抵抗，(2)哪些基因与IR子代以及患有高血压和高脂血症的家系中线粒体活性/含量降低有关，这似乎是由于线粒体tRNA/ILE中的一个新的同质突变引起的。(3)这些患者和胰岛素抵抗的老年受试者的脑线粒体代谢是否受到影响？这些问题将通过这三个项目的首席研究人员之间的合作互动来解决，这三个项目如下：(项目1)-舒尔曼博士将阐述线粒体功能障碍在胰岛素抵抗后代胰岛素抵抗发病机制中的作用。该项目建立在他的团队的初步数据基础上，该数据表明，这些人的心肌细胞内脂质含量增加，这可以归因于线粒体活动的减少。该项目将使用13C/31P/1H MRS进一步探索这些人肝脏和肌肉中的线粒体功能，并结合通过细胞和分子方法对肌肉组织进行直接检查，以使用新的LC/MSIMS方法直接量化线粒体含量、胰岛素信号和蛋白质磷酸化。(项目2)-Lifton博士将检查从IR后代和胰岛素敏感对照受试者获得的肌肉活检样本中的核和线粒体DNA 为了确定导致线粒体功能/含量降低和胰岛素抵抗的基因，在项目1中进行了特征描述。该项目将检验一种假说，即调控线粒体生物发生的基因改变是导致胰岛素抵抗的原因。该项目还将进一步描述高血压和高脂血症患者的特征，他的团队的初步数据表明，这是由线粒体tRNA/ILE中的一种新的同质突变引起的。该计划由计划教职员工和研究人员的频繁会议协调，他们将这些不同的方法捆绑在一起，以解决共同的目标。

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.