Role of estrogen-related receptors in cardiac and skeletal muscle

雌激素相关受体在心肌和骨骼肌中的作用

• 批准号: 7259660
• 负责人: JANICE M HUSS
• 金额: $ 30.99万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-24 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7259660
• 关键词: Adipose tissue; Adult; Biogenesis; Cardiac; Cell Line; Cell Respiration; Cell model; Complement; Coupled; Cues; Development; Diabetes Mellitus; Disease; Energy Metabolism; Enzyme Gene; Enzymes; Estrogens; Family; Fatty Acids; Gene Expression; Gene Expression Microarray Analysis; Gene Expression Profiling; Gene Expression Regulation; Gene Targeting; Generations; Genes; Glucose; Heart; Heart failure; Homeostasis; In Vitro; Insulin Resistance; Knock-out; Lead; Link; Liver; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Mus; Muscle; Muscle Cells; Muscle function; Mutation; Myocardial Ischemia; Myocardium; Myopathy; Non-Insulin-Dependent Diabetes Mellitus; Normal tissue morphology; Nuclear Receptors; Obesity; Pathway interactions; Peroxisome Proliferators; Physiological; Play; Process; Protein Isoforms; Protein Overexpression; Regulation; Regulatory Pathway; Respiration; Role; Signal Transduction; Skeletal Muscle; Small Interfering RNA; Stimulus; Testing; Thinking; Tissues; Transcription Coactivator; Transcriptional Regulation; Workload; adenoviral-mediated; age related; base; cell growth regulation; chromatin immunoprecipitation; fatty acid oxidation; gain of function; gene discovery; human disease; in vivo; in vivo Model; loss of function; mouse model; muscle metabolism; novel; oxidation; programs; promoter; receptor; receptor function; respiratory enzyme; response; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Appropriate regulation of cellular metabolic programs involved in energy (ATP) generation is essential for normal tissue development and homeostasis. ATP generation in heart and slow-twitch skeletal muscle involves primarily oxidative metabolism of fatty acids and glucose within the mitochondrion. The capacity for mitochondria! ATP generation and the selection of energy substrates in heart and skeletal muscle is regulated by developmental, physiological, and environmental cues that signal coordinated changes in the levels of enzymes involved these processes. Perturbations of appropriate regulation lead to changes in mitochondrial metabolism and substrate selection linked to heart and skeletal muscle insulin resistance and diabetes, heart failure and age-related declines in muscle function. Nuclear receptor (NR) transcription factors and their coactivator, PGC-1a, play a central role in regulating energy metabolism in skeletal muscle, heart, brown adipose and liver, by coordinating changes in metabolic enzyme gene expression. The estrogen-related receptors (ERR), ERRa and ERRg, have been implicated as important metabolic regulators in heart and skeletal muscle, due to their high expression in these tissues and their responsiveness to physiologic cues that increase energy metabolism. In order to understand the broad regulatory program downstream of ERRs in muscle, we propose using in vitro cell models and genetically-modified mouse models of ERRa and ERRg gain- and loss-of-function. We will analyze these models with gene expression profiling coupled with chromatin immunoprecipitation to identify target genes for ERRs. Based upon gene targets identified to date, we propose that ERRs are essential activators of heart and skeletal muscle energy metabolism that play particularly important function in developmental switches in myocyte metabolic programs. We assess the regulation of metabolism using models in which ERR isoforms are selectively activated by overexpression or inhibited by gene targeting or small-interfering RNA. The characterization of ERR function in cardiac and skeletal muscle has important implications for disease states, including heart failure and myocardial ischemia, type 2 diabetes, and obesity. Our findings will elucidate the potential for ERRs as therapeutic targets for widespread human diseases associated with metabolic dysregulation.

描述（由申请人提供）：对涉及能量（ATP）生成的细胞代谢程序进行适当调节对于正常组织发育和体内平衡至关重要。心脏和慢肌骨骼肌中 ATP 的生成主要涉及线粒体内脂肪酸和葡萄糖的氧化代谢。线粒体的能力！心脏和骨骼肌中 ATP 的生成和能量底物的选择受到发育、生理和环境线索的调节，这些线索发出参与这些过程的酶水平的协调变化信号。适当调节的干扰会导致线粒体代谢和底物选择的变化，这些变化与心脏和骨骼肌胰岛素抵抗、糖尿病、心力衰竭和与年龄相关的肌肉功能下降有关。核受体 (NR) 转录因子及其共激活子 PGC-1a 通过协调代谢酶基因表达的变化，在调节骨骼肌、心脏、棕色脂肪和肝脏的能量代谢中发挥核心作用。雌激素相关受体 (ERR)、ERRa 和 ERRg 被认为是心脏和骨骼肌中重要的代谢调节因子，因为它们在这些组织中高表达，并且对增加能量代谢的生理信号有反应。为了了解肌肉中 ERR 下游的广泛调控程序，我们建议使用 ERRa 和 ERRg 功能获得和丧失的体外细胞模型和转基因小鼠模型。我们将通过基因表达谱与染色质免疫沉淀结合分析这些模型，以确定 ERR 的靶基因。根据迄今为止确定的基因靶标，我们认为 ERR 是心脏和骨骼肌能量代谢的重要激活剂，在心肌细胞代谢程序的发育开关中发挥特别重要的作用。我们使用模型评估代谢调节，其中 ERR 同种型通过过度表达选择性激活或通过基因靶向或小干扰 RNA 抑制。心脏和骨骼肌中 ERR 功能的表征对疾病状态具有重要意义，包括心力衰竭和心肌缺血、2 型糖尿病和肥胖。我们的研究结果将阐明 ERR 作为与代谢失调相关的广泛人类疾病的治疗靶点的潜力。