MRS Studies of Brain Mitochondrial Function in Metabolic Syndrome

代谢综合征脑线粒体功能的 MRS 研究

• 批准号: 6844967
• 负责人: Douglas Lyle Rothman
• 金额: $ 8.92万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844967
• 关键词: bioimaging /biomedical imaging; brain imaging /visualization /scanning; brain metabolism; clinical research; human subject; liver metabolism; magnetic resonance imaging; metabolic syndrome; mitochondrial DNA; muscle metabolism; neural degeneration; noninsulin dependent diabetes mellitus

The central hypothesis of this program project is that altered mitochondrial function is a key determinant of metabolic syndrome. However while metabolic syndrome has been extensively characterized in muscle, liver, kidney and pancreas, little is known about how it impacts brain function. The potential importance of understanding the impact of metabolic syndrome on brain function is highlighted by two converging lines of evidence. Firstly, recent studies have strongly implicated impaired brain mitochondrial function in a host of neurodegenerative diseases, including Alzheimer's and temporal lobe epilepsy. Secondly, epidemiological studies have found a several fold enhancement in the total incidence of neurodegenerative diseases in patients with type 2 Diabetes Metlitus. Reduced brain mitochondria in people with severe insulin resistance may be a factor in this increased susceptibility. In project 3 we will take advantage of our recent developments of MRS methods for non-invasively imaging brain mitochondrial metabolic function to assess whether it is altered in three groups of subjects with metabolic syndrome. These groups are 1) insulin resistant offspring of parents with Type II diabetes, 2) elderly subjects and 3) patients with an identified mutation in a gene coding for mitochondrial tRNA. Recent MRS studies by the Shulman laboratory have shown that all three groups have altered muscle mitochondrial metabolism. Our general hypothesis in this project is that there are similar alterations in brain mitochondrial metabolism in the brain of these subjects as in the muscle and liver. This project will )rovide the first comprehensive study of metabolic syndrome to brain, and may provide new insight nto why subjects with metabolic syndrome are at increased risk of neurodegenerative disease.

该项目的中心假设是改变线粒体功能是关键 代谢综合征的决定因素。然而，尽管代谢综合征已被广泛 其特征在于肌肉、肝脏、肾脏和胰腺，但人们对其如何影响大脑知之甚少 功能。了解代谢综合征对大脑影响的潜在重要性 两条证据线汇聚强调了其功能。首先，最近的研究强烈 大脑线粒体功能受损与许多神经退行性疾病有关，包括阿尔茨海默病和颞叶癫痫。其次，流行病学研究发现，2 型糖尿病患者神经退行性疾病的总发病率增加了几倍。患有严重胰岛素抵抗的人脑线粒体减少可能是易感性增加的一个因素。在项目 3 中，我们将利用我们最近的 MRS 方法的发展，用于对脑线粒体代谢功能进行非侵入性成像，以评估三组代谢综合征受试者的线粒体代谢功能是否发生改变。这些群体是 1) 患有 II 型糖尿病的父母的胰岛素抵抗后代，2) 老年受试者和 3) 线粒体 tRNA 编码基因已发现突变的患者。舒尔曼实验室最近的 MRS 研究表明，所有三组人都改变了肌肉线粒体代谢。我们在这个项目中的总体假设是，这些受试者大脑中的线粒体代谢与肌肉和肝脏中存在类似的变化。该项目将首次对大脑代谢综合征进行全面研究，并可能为为什么患有代谢综合征的受试者患神经退行性疾病的风险增加提供新的见解。