Amphiregulin Signaling in Perioperative Cardio-Protection

描述(由申请人提供)：本研究提案的主要目的是确定两调节素信号在围术期心肌缺血保护中的功能作用。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，我们开始确定可能介导心脏保护的HIF依赖的靶基因。对条件性HIF2A缺失的小鼠的研究表明，我们倾向于两亲调节蛋白(AREG)。事实上，用AREG重组Hif2aloxP/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的产生和通过其受体ErbB1的信号传递对急性缺血的心脏保护作用。我们建议研究AREG在心肌缺血过程中的转录调控，并通过检测人类心脏组织中AREG的转录和蛋白水平来测试这一途径与人类疾病的相关性。此外，我们还将研究AREG在ARG-/-小鼠心肌缺血过程中的功能作用。最后，我们将利用一个肌细胞特异性缺失ErbB1的小鼠系来研究AREG受体ErbB1的表达和功能。这些研究对于开发新的治疗方法以预防或减轻大手术患者心肌缺血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.