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，但该相同的细胞器是活性氧（ROS）（一种内源性毒素）的主要来源。线粒体！功能障碍与包括2型糖尿病、肥胖症和神经变性疾病在内的许多疾病有关。最近的工作，包括以前由该基金资助的许多工作，已经表明PGC-1转录辅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。这项新的资助提出了探索PGC-1 a在正常生理学和许多涉及线粒体功能障碍的疾病中的作用的实验。我们的第一个目标是使用我们已经制备的肌肉特异性KO来确定PGC-1 a在小鼠糖尿病和肥胖症发展中的作用。小鼠将在基础状态下以及在高脂肪喂养和衰老的挑战下进行研究。将通过葡萄糖耐量试验和高胰岛素-正常血糖钳夹来测量葡萄糖稳态。我们还将研究在PGC-1 a存在和不存在的情况下的肌肉纤维类型和跑步性能。我们的第二个目标将集中在AMP激酶和PGC-1 a之间的体外和体内合作。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具有抑制ROS形成的强大能力，因为它激活线粒体呼吸。事实上，ROS诱导ROS解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，并且相反地，试图理解PGC-1 a停靠以开启ROS解毒程序的转录因子。我们还将尝试创建具有突变PGC-1基因的小鼠品系，该突变PGC-1基因仍然可以调节OXPHOS而不是ROS，并研究其在代谢疾病中的作用。这些研究应该提供新的机会，以调节氧化代谢的方式，允许新的方法来治疗一些重要的人类疾病。