Amphiregulin Signaling in Perioperative Cardio-Protection

描述（由申请人提供）：本研究计划的主要目的是确定双调节蛋白信号在围手术期心肌缺血心脏保护中的功能作用。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，我们着手鉴定可能介导心脏保护的HIF依赖性靶基因。对条件Hif2a缺失小鼠的研究指向了双调节蛋白（AREG）。事实上，Hif2aloxP/loxP Myosin Cre+小鼠与AREG的重建与它们的表型逆转有关，并在野生型小鼠中提供心脏保护。因此，我们假设AREG的产生和通过其受体ErbB1传递的信号传递了急性缺血时的心脏保护作用。我们拟研究心肌缺血时AREG的转录调控，并通过检测人心脏组织中AREG转录物和蛋白水平来检测该通路与人类疾病的相关性。此外，我们将研究AREG -/-小鼠心肌缺血时AREG的功能作用。最后，我们将利用具有肌细胞特异性ErbB1缺失的小鼠细胞系研究AREG受体ErbB1的表达和功能。这些研究对于开发新的治疗方法来预防或减轻大手术患者心肌缺血性组织损伤具有重要意义。

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.