PGC-1 and Nuclear Receptors in Adaptive Thermogenesis

PGC-1 和核受体在适应性产热中的作用

• 批准号: 7998078
• 负责人: BRUCE M. SPIEGELMAN
• 金额: $ 27.26万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-21 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7998078
• 关键词: Aging; Alleles; Biology; Cell Respiration; Cells; Collaborations; Data; Development; Diabetes Mellitus; Disease; Docking; Drug Metabolic Detoxication; Electron Transport; Environment; Enzymes; Euglycemic Clamping; Eukaryota; Event; Fatty acid glycerol esters; Fiber; Functional disorder; Funding; Gene Expression; Generations; Genes; Glucose Clamp; Glucose tolerance test; Grant; Heart Diseases; Hyperactive behavior; In Vitro; Insulin Resistance; Knock-out; Link; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Molecular; Mouse Strains; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle function; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Organelles; Oxygen; Performance; Phosphorylation; Phosphotransferases; Physiology; Play; Reactive Oxygen Species; Respiration; Role; Running; Source; Thermogenesis; Time; Tissues; Toxin; Transcription Coactivator; Work; adenylate kinase; base; blood glucose regulation; extracellular; feeding; human disease; human morbidity; in vivo; mitochondrial dysfunction; mutant; novel strategies; programs; promoter; research study; transcription factor

DESCRIPTION (provided by applicant): Eukaryotes rely on mitochondria to produce ATP efficiently, yet this same organelle is the major source of reactive oxygen species (ROS), an endogenous toxin. Mitochondria! dysfunction has been associated with many disorders including type 2 diabetes, obesity and neurodegenerative diseases. Recent work, including much that was funded previously by this grant, has shown that the PGC-1 transcriptional coactivators link mitochondrial function to the external and extracellular environment in many tissues. This new grant proposes experiments that probe the role of PGC-1 a in normal physiology and in a number of diseases involving mitochondrial dysfunction. Our first Aim will determine the role PGC-1 a in the development of diabetes and obesity in mice, using a muscle-specific KO we have made. Mice will be studied in the basal state and under challenges of high-fat feeding and aging. Glucose homeostasis will be measured with glucose tolerance tests and hyperinsulinemic-euglycemic clamps. We will also study muscle fiber-types and running performance in the presence and absence of PGC-1 a. Our second Aim will be focused on the collaboration in vitro and in vivo between AMP kinase and PGC-1 a. Our new data indicates that AMPK directly phosphorylates PGC-1 a in vitro and in cells, and requires PGC-1 a to modulate certain programs of gene expression. In our third Aim, we have recently found that PGC-1 a has a powerful ability to suppress the formation of ROS, as it activates mitochondrial respiration. Indeed the ability of ROS to induce a ROS detoxification program is dependent on PGC-1 a and PGC-1 p. We will determine the key molecular events that allow ROS to induce PGC-1 a and, conversely, attempt to understand the transcription factors on which PGC-1 a docks to turn on the ROS detoxification program. We will also attempt to create strains of mice with a mutant PGC-1 a gene which can still regulate OXPHOS but not ROS, and study effects in metabolic disease. These studies should provide new opportunities to modulate oxidative metabolism in ways that allow for new approaches to some important human diseases.

描述（由申请人提供）：真核生物依靠线粒体有效地产生ATP，但相同的细胞器是内源性毒素的活性氧（ROS）的主要来源。线粒体！功能障碍与许多疾病有关，包括2型糖尿病，肥胖和神经退行性疾病。最近的工作，包括以前由该赠款资助的许多工作，表明PGC-1转录共激活因子将线粒体功能与许多组织中的外部和细胞外环境联系起来。这项新赠款提出了探测PGC-1 A在正常生理学以及许多涉及线粒体功能障碍的疾病中的作用的实验。我们的第一个目的将确定使用我们所做的肌肉特异性KO，PGC-1 A在小鼠糖尿病和肥胖的发展中的作用。将在基础状态下研究小鼠，并在高脂喂养和衰老的挑战下进行研究。葡萄糖稳态将通过葡萄糖耐受性测试和高胰岛素 - 糖血糖夹子进行测量。我们还将在PGC-1 a的存在和不存在的情况下研究肌肉纤维类型和跑步性能。我们的第二个目标将集中于AMP激酶和PGC-1 a之间的体外和体内协作。我们的新数据表明，AMPK在体外和细胞中直接磷酸化PGC-1 A，并且需要PGC-1 A来调节某些基因表达程序。在我们的第三个目标中，我们最近发现，PGC-1 A具有强大的能力来抑制ROS的形成，因为它激活了线粒体呼吸。实际上，ROS诱导ROS排毒程序的能力取决于PGC-1 A和PGC-1 P。我们将确定允许ROS诱导PGC-1 A的关键分子事件，并相反，试图了解PGC-1 A码头开启ROS ROS排毒程序的转录因子。我们还将尝试用突变体PGC-1 A基因创建小鼠菌株，该基因仍然可以调节OXPHOS，而不能调节ROS，并在代谢疾病中进行研究影响。这些研究应提供新的机会，以允许对某些重要人类疾病的新方法进行调节氧化代谢。