Mitochrondrial Dysfunction: Role in Metabolic Syndrome

该计划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。该项目涉及多个部门成员之间的协作互动，并由三个核心设施组织成三个项目。临床生理学、生物化学、人类遗传学、细胞与分子生物学和核磁共振波谱学（MRS）领域的专家将专注于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导致2型糖尿病父母（IR后代）的年轻瘦血糖正常的后代肌肉/肝脏脂肪堆积和胰岛素抵抗？(2)哪些基因导致IR后代和高血压和高脂血症家庭的线粒体活性/含量降低，这似乎是由于线粒体tRNA/ile的一种新的同质突变。(3)这些患者以及胰岛素抵抗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初步数据的基础上，这些数据表明，这些个体的细胞内脂质含量增加，这可归因于线粒体活性降低。该项目将使用13C/31p/1H MRS进一步探索这些个体的肝脏和肌肉中的线粒体功能，并结合细胞和分子方法直接检测肌肉组织，使用新颖的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组获得的肌肉活检样本中的核和线粒体DNA

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.