Contractile Regulation of Cardiocyte Protein Synthesis

心肌细胞蛋白质合成的收缩调节

• 批准号: 8696789
• 负责人: PAUL J MCDERMOTT
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696789
• 关键词: Address; Adult; Adverse effects; Anoxia; Binding; Biogenesis; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cessation of life; Characteristics; Companions; Complex; Contracts; Coronary artery; Coronary heart disease; Coupled; Data; Defect; Down-Regulation; ERR1 protein; Elements; Energy Metabolism; Enzymes; Family Felidae; Feedback; Funding; Gene Expression; Gene Targeting; Generations; Genes; Genetic Transcription; Goals; Heart; Heart Diseases; Heart failure; Human; Hypoxia; In Vitro; Indium; Injury; Ischemia; Ligands; Link; Messenger RNA; Metabolic; Metabolic Pathway; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Necrosis; Nuclear Receptors; Orphan; Outcome; Oxidative Phosphorylation; Oxidative Stress; Oxygen; PPAR gamma; Pathway interactions; Patients; Peptide Initiation Factors; Physiological; Population; Protein Biosynthesis; Protein Isoforms; Regulation; Reperfusion Injury; Reperfusion Therapy; Role; Structure; Therapeutic; Translations; United States; Untranslated Regions; Ventricular Remodeling; Veterans; deprivation; estrogen-related receptor; fatty acid metabolism; fatty acid oxidation; glucose metabolism; improved; in vivo; in vivo Model; injured; mRNA Stability; meetings; member; mortality; programs; receptor; response; statistics; transcription factor

DESCRIPTION (provided by applicant): Partial or complete occlusion of a coronary artery creates ischemia, thereby exposing the myocardium to either an insufficient supply of oxygen (hypoxia) or a complete lack of oxygen (anoxia). Consequently, myocardial injury and necrosis occur that are dependent on multiple variables such as the extent and duration of oxygen deprivation and the adverse effects produced in cardiomyocytes during reoxygenation of the myocardium (ischemia/reperfusion). The overall energetic capacity of cardiomyocytes under normal physiological conditions is coupled to fatty acid oxidation for metabolic fuel and to mitochondrial oxidative phosphorylation for ATP generation. To minimize the adverse effects of insufficient oxygen on cardiac structure and function, the myocardium adapts by activating glycolytic pathways to fuel energy metabolism in the cardiomyocyte. This switch to glucose metabolism is a common feature of pathological remodeling that develops during ischemic heart disease and other causes of heart failure. This gene program for energy metabolism is regulated by Estrogen-Related Receptors (ERR), a member of the nuclear receptor superfamily that activates transcription of a wide array of target genes required for mitochondrial biogenesis, fatty acid metabolism and oxidative phosphorylation. Specifically, these studies will define the causes that result in down-regulation of ERR target genes by examining molecular mechanisms that regulate translational efficiency and/or stability of ERR mRNA isoforms in response to hypoxia and reoxygenation of adult cardiocytes. ERR mRNA has both structural features and sequence elements in the 54-UTR and 34-UTR that are characteristic of translationally regulated mRNAs. These include a 54-UTR that is G-C rich (82%) with extensive secondary structure in the form of a large, stable hairpin loop near the 54-cap, and a relatively long 34-UTR that has possible AU-rich elements involved in translation-linked mRNA stability. The preliminary data have revealed that ERR1 expression is regulated in adult cardiomyocytes during hypoxia and reoxygenation at the level of translation. These studies will examine the effects of hypoxia and reoxygenation in regulating translational efficiency and stability of ERR mRNA isoforms in adult feline cardiomyocytes that are electrically stimulated to contract continuously at defined physiological parameters. Companion studies will be done using a murine model of myocardial ischemia and ischemia/reperfusion injury establish the physiological significance of the adult cardiomyocyte model to oxidative stress in vivo. The hypothesis is that expression of ERR1 is controlled during hypoxia and reoxygenation in the adult cardiomyocyte by mechanisms that modify translation and/or stability of ERR1 mRNA. The specific aims are: 1) to determine the mechanism(s) that regulate expression of ERRs during hypoxia and hypoxia/reoxygenation of adult cardiomyocytes in vitro and during myocardial remodeling produced in response to ischemia and ischemia/reperfusion injury in a murine model in vivo; 2) to examine the role of specific elements in the 54-UTR and/or 34-UTR in regulating translation and stability of ERR1 mRNA in adult cardiomyocytes; 3) to examine how modifying activity of initiation factors can alter expression of ERR1 and its activity as determined by downstream effects on target genes. The long term goal of these studies to gain a better understanding of the mechanisms that contribute to adaptive changes in myocardial gene expression during adverse remodeling, and ultimately devise therapeutic strategies that can reverse the transition to heart failure and improve outcomes for Veterans and other patients in the U.S. population.

描述（由申请人提供）： 冠状动脉的部分或完全闭塞造成缺血，从而使心肌暴露于氧供应不足（缺氧）或完全缺氧（缺氧）。因此，心肌损伤和坏死的发生取决于多个变量，例如缺氧的程度和持续时间以及心肌再氧合（缺血/再灌注）期间在心肌细胞中产生的不良作用。在正常生理条件下心肌细胞的总体能量能力与脂肪酸氧化代谢燃料和线粒体氧化磷酸化ATP的产生有关。为了最大限度地减少缺氧对心脏结构和功能的不利影响，心肌通过激活糖酵解途径来适应心肌细胞中的能量代谢。这种向葡萄糖代谢的转变是缺血性心脏病和其他心力衰竭原因中病理性重塑的共同特征。这种用于能量代谢的基因程序由雌激素相关受体（ERR）调节，雌激素相关受体是核受体超家族的成员，其激活线粒体生物发生、脂肪酸代谢和氧化磷酸化所需的多种靶基因的转录。具体而言，这些研究将通过检查调节ERR mRNA同种型的翻译效率和/或稳定性的分子机制来确定导致ERR靶基因下调的原因，以响应成年心肌细胞的缺氧和再氧合。ERR mRNA在54-UTR和34-UTR中具有结构特征和序列元件，这是受调控mRNA的特征。这些包括富含G-C（82%）的54-UTR，其具有在54-帽附近以大的稳定发夹环形式存在的广泛二级结构，以及相对长的34-UTR，其具有可能涉及与发夹连接的mRNA稳定性的富含AU的元件。初步数据显示，ERR 1的表达在缺氧和复氧过程中在翻译水平上受到调节。这些研究将检查缺氧和复氧在调节ERR mRNA亚型在成年猫心肌细胞中的翻译效率和稳定性中的作用，所述成年猫心肌细胞被电刺激以在限定的生理参数下连续收缩。将使用心肌缺血和缺血/再灌注损伤的鼠模型进行伴随研究，以建立成年心肌细胞模型对体内氧化应激的生理意义。假设ERR 1的表达在成人心肌细胞缺氧和复氧过程中通过改变ERR 1 mRNA的翻译和/或稳定性的机制来控制。具体目标是：1）确定在体外成体心肌细胞的缺氧和缺氧/复氧期间以及在体内鼠模型中响应于缺血和缺血/再灌注损伤而产生的心肌重塑期间调节ERR表达的机制; 2）检查54-UTR和/或34-UTR中的特定元件在调节成体心肌细胞中ERR 1 mRNA的翻译和稳定性中的作用; 3）研究起始因子的修饰活性如何改变ERR 1的表达及其活性，如通过对靶基因的下游作用所确定的。这些研究的长期目标是更好地了解不良重塑期间心肌基因表达适应性变化的机制，并最终设计出可以逆转心力衰竭转变并改善美国退伍军人和其他患者结局的治疗策略。