Amphiregulin Signaling in Perioperative Cardio-Protection

双调蛋白信号传导在围手术期心脏保护中的作用

• 批准号: 9012107
• 负责人: Holger K. Eltzschig
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9012107
• 关键词: 6-Phosphofructo-2-kinase; Acute; Address; Amphiregulin; Antibodies; Area; Attenuated; Brain Hypoxia-Ischemia; Carbohydrates; Cardiac; Cardiac Myocytes; Constitution; Data; Dose; EGFR gene; Embryonic Development; Epidermal Growth Factor; Funding; Gene Targeting; Genetic; Genetic Models; Goals; HIF1A gene; Health; Human; Hypoxia; Infarction; Injury; Ischemia; Mediating; Metabolic; Molecular; Morbidity - disease rate; Mus; Muscle Cells; Myocardial Ischemia; Myocardial Reperfusion; Myocardial tissue; Myocardium; Myosin ATPase; Operative Surgical Procedures; Organ; Outcome; Oxygen; Pathway interactions; Patients; Perioperative; Phenotype; Phosphorylation; Positioning Attribute; Prevention; Production; Protein Isoforms; Proteins; RNA Binding; Reading; Recombinants; Research; Research Design; Research Proposals; Role; Route; Signal Transduction; Testing; Time; Tissues; Transcript; Transcriptional Regulation; Wild Type Mouse; base; design; experience; human disease; in vivo; mortality; myocardial hypoxia; novel therapeutic intervention; novel therapeutics; prevent; receptor; response; transcription factor

DESCRIPTION (provided by applicant): The main goal of this research proposal is to identify the functional role of amphiregulin signaling in perioperative cardio-protection from myocardial ischemia. Transcriptional responses elicited by ischemia/hypoxia involve hypoxia inducible transcription factors (HIFs). Here, we set out to identify HIF- dependent target genes that could mediate cardio-protection. Studies in mice with conditional Hif2a deletion pointed us towards amphiregulin (AREG). Indeed, re-constitution of Hif2aloxP/loxP Myosin Cre+ mice with AREG was associated with a reversal of their phenotype and provided cardio-protection in wild-type mice. Therefore, we hypothesize that AREG production and signaling through its receptor ErbB1 conveys cardio-protection from acute ischemia. We propose to study the transcriptional control of AREG during myocardial ischemia, and test the relevance of this pathway on human disease by examining AREG transcript and protein levels in human cardiac tissues. Moreover, we will examine the functional role of AREG during myocardial ischemia in Areg-/- mice. Finally, we will study expression and function of the AREG receptor ErbB1 utilizing a mouse line with myocyte-specific deletion of ErbB1. These studies are significant for developing novel therapeutic approaches to prevent or attenuate ischemic tissue injury of the myocardium in patients undergoing major surgery.

描述（由申请人提供）：本研究提案的主要目标是确定双调蛋白信号在围手术期心肌缺血保护中的功能作用。由缺血/缺氧引起的转录反应涉及缺氧诱导转录因子（HIF）。在这里，我们着手鉴定可以介导心脏保护的HIF依赖性靶基因。在具有条件性Hif 2a缺失的小鼠中的研究将我们指向双调蛋白（AREG）。事实上，用AREG重建Hif 2aloxP/loxP肌球蛋白Cre+小鼠与其表型逆转相关，并在野生型小鼠中提供心脏保护。因此，我们假设AREG的产生和信号通过其受体ErbB 1传递心脏保护免受急性缺血。我们建议研究AREG在心肌缺血过程中的转录调控，并通过检测人心脏组织中AREG的转录和蛋白水平来测试该途径与人类疾病的相关性。此外，我们将研究AREG在Areg-/-小鼠心肌缺血过程中的功能作用。最后，我们将利用肌细胞特异性缺失ErbB 1的小鼠系研究AREG受体ErbB 1的表达和功能。这些研究对于开发新的治疗方法以预防或减轻接受大手术的患者的心肌缺血性组织损伤具有重要意义。