Nuclear Orphan Receptor, COUP-TFII, in Energy Metabolism and Disease

核孤儿受体，COUP-TFII，在能量代谢和疾病中的应用

• 批准号: 8495646
• 负责人: SOPHIA Y. TSAI
• 金额: $ 37.25万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495646
• 关键词: Address; Adult; Binding Sites; CCL4 gene; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cessation of life; ChIP-seq; Coupled; Disease; Energy Metabolism; Energy-Generating Resources; Enzymes; Essential Fatty Acids; Fatty Acids; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Glucose; Health Hazards; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Homeostasis; Lead; Lipids; Mediating; Medical; Messenger RNA; Metabolic; Metabolic Pathway; Mitochondria; Modeling; Molecular; Mus; Myocardial; Myocardium; Nuclear Orphan Receptor; Nuclear Receptors; Organ; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Phenotype; Play; Recruitment Activity; Regulation; Role; Signal Transduction; Societies; Source; Stress; Testing; Tissues; United States; Work; apoAI regulatory protein-1; cell type; cohort; fatty acid metabolism; fetal; hemodynamics; in vivo; member; mouse model; overexpression; oxidation; preference; pressure; programs; public health relevance; trafficking

DESCRIPTION (provided by applicant): Heart failure is a major medical problem of the modern society and 1 in 9 deaths in the United States (2007) is caused by heart failure. The heart is a high energy-demanding organ that uses fatty acids as the major fuel source. However, under stressed conditions such as cardiomyopathy, the stressed myocardium often switches energy usage preference from lipid to glucose. Intriguingly, elevated expression of COUP-TFII was observed in stressed hearts of non-ischemic cardiomyopathy patients and also in a pressure overload mouse model. To investigate the role of COUP-TFII in cardiac dysfunction, we generated a mouse model over-expressing COUP- TFII specifically in the cardiomyocytes. Our preliminary results showed that over-expression of COUP-TFII results in the suppression of the expression of key enzymes essential for fatty acid trafficking and oxidation, suggesting a switch of fuel usage. The expression of many enzymes involved in fatty acid metabolism is regulated by the PGC/ERR axis. Interestingly, we also showed reduced expression of PGC1/ and ERR/, thus strongly implicating COUP-TFII as a regulator for controlling the PGC/ERR axis to alter fuel usage and mitochondrial function, leading to dysregulation of energy metabolism. Interestingly, we also showed that mice over-expressing SRC-2 also reduces lipid usage in the cardiac muscle, phenotypes analogous to COUP-TFII over-expression. Taken together, we hypothesize that COUP-TFII and SRC-2 act jointly to control cardiac function through modulating the expression of key genes involved in energy metabolism. To dissect the role of COUP-TFII and SRC-2 in the dysregulation of cardiac energy metabolism, three specific aims are proposed: 1. Dissect the role of COUP-TFII in the regulation of cardiac energy metabolism; 2. Identify pathways regulated by COUP-TFII in the heart and 3. Investigate the functional interaction between COUP-TFII and SRC- 2 in regulating cardiac fuel usage. These studies will increase our understanding of how COUP-TFII and SRC-2 jointly regulate transcriptional networks in cell types that are pivotal in the regulation of metabolic pathways that govern energy homeostasis in vivo.

描述（由申请人提供）：心力衰竭是现代社会的主要医学问题，2007年美国每9例死亡中就有1例是由心力衰竭引起的。心脏是一个高能量需求的器官，脂肪酸是其主要的能量来源。然而，在诸如心肌病等应激条件下，应激心肌通常会将能量使用偏好从脂质转换为葡萄糖。有趣的是，在非缺血性心肌病患者和压力过载小鼠模型的应激心脏中观察到COUP-TFII的表达升高。为了研究COUP-TFII在心功能障碍中的作用，我们在心肌细胞中建立了过表达COUP-TFII的小鼠模型。我们的初步结果表明，COUP-TFII的过度表达导致脂肪酸运输和氧化所必需的关键酶的表达受到抑制，这表明燃料使用的改变。许多参与脂肪酸代谢的酶的表达受PGC/ERR轴的调控。有趣的是，我们还发现PGC1/和ERR/的表达减少，因此强烈暗示COUP-TFII作为控制PGC/ERR轴的调节剂，改变燃料使用和线粒体功能，导致能量代谢失调。有趣的是，我们还发现过表达SRC-2的小鼠也减少了心肌中的脂质使用，表型类似于COUP-TFII过表达。综上所述，我们假设COUP-TFII和SRC-2通过调节参与能量代谢的关键基因的表达来共同控制心功能。为了剖析COUP-TFII和SRC-2在心脏能量代谢失调中的作用，提出了三个具体目标：1。分析COUP-TFII在心脏能量代谢调节中的作用；2. 2 .确定COUP-TFII在心脏和研究COUP-TFII和SRC- 2在调节心脏燃料使用中的功能相互作用。这些研究将增加我们对COUP-TFII和SRC-2如何共同调节细胞类型中的转录网络的理解，这些转录网络在调节体内能量稳态的代谢途径中起关键作用。