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，但同样的细胞器是活性氧 (ROS)（一种内源性毒素）的主要来源。线粒体！功能障碍与许多疾病有关，包括 2 型糖尿病、肥胖症和神经退行性疾病。最近的工作，包括之前由该资助资助的大部分工作，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。这项新资助计划开展实验，探索 PGC-1a 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。我们的第一个目标是使用我们制作的肌肉特异性 KO 来确定 PGC-1a 在小鼠糖尿病和肥胖发展中的作用。将在基础状态下以及高脂肪喂养和衰老的挑战下对小鼠进行研究。葡萄糖稳态将通过葡萄糖耐量试验和高胰岛素正常血糖钳来测量。我们还将研究存在和不存在 PGC-1a 的情况下的肌纤维类型和跑步表现。我们的第二个目标将集中于 AMP 激酶和 PGC-1a 之间的体外和体内合作。我们的新数据表明，AMPK 在体外和细胞内直接磷酸化 PGC-1a，并需要 PGC-1a 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-1a 具有强大的抑制 ROS 形成的能力，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 ROS 诱导 PGC-1a 的关键分子事件，并尝试了解 PGC-1a 停靠的转录因子以开启 ROS 解毒程序。我们还将尝试培育具有突变 PGC-1 基因的小鼠品系，该基因仍可以调节 OXPHOS 但不能调节 ROS，并研究其对代谢疾病的影响。这些研究应该为调节氧化代谢提供新的机会，从而为一些重要的人类疾病提供新的治疗方法。