REGULATION OF MONOCYTE RECRUITMENT INTO THE ISCHEMIC MYOCARDIUM BY THE ACE2 AXIS

描述(由申请人提供)：本提案的目标是将首席研究员(PI)发展成为心血管研究领域的独立内科科学家。 PI已经接受了免疫学基础科学领域的密集博士培训和心血管研究方面的重要额外培训，包括基础科学和翻译性质的培训。PI已经完成了内科的临床培训，目前正在完成心脏病学分专业培训的最后一年。以下五年的职业发展计划将为PI提供进一步的完善和培训，以便在奖项结束时获得研究独立性。华盛顿大学心脏科主任道格拉斯·曼博士将指导PI。曼博士是公认的心肌炎症领域的领导者，他拥有丰富的经验，从确定促炎细胞因子在心力衰竭中的作用，到利用这些知识并根据他的结果带头进行临床试验。因此，他是一个成功的内科科学家的完美范例，能够将基础科学研究转化为临床领域。PI将利用这种指导以及美国顶尖学术机构之一华盛顿大学可用的大量基础科学和临床资源，以定义一个与临床相关的基础科学研究的新领域。心肌梗死(MI)是美国发病率和死亡率的主要原因，我们对其潜在机制的了解仍不完全。单核细胞是心肌梗死后第一周渗入心肌的主要细胞类型。不幸的是，尽管过度募集会导致梗塞愈合受损，但人们对控制单核细胞募集的调控因素知之甚少。最近的证据表明，血管紧张素II(AngII)的病理性激活直接参与了缺血损伤后单核细胞的募集。血管紧张素转换酶2(ACE2)是一种重要的内源性血管紧张素转换酶(Angii)反向调节因子，它不仅能降解Angii，还能产生Ang1-7，这是一种与Mas受体(MASR)结合的生物活性多肽。增强ACE2/Ang1-7/MASR轴的任何组成部分的活性均可限制心肌缺血损伤，然而ACE2轴与单核细胞募集之间的相互作用尚未得到评估。我们假设单核细胞定位的ACE2/Ang1-7/MASR轴存在，这是防止心肌缺血后单核细胞过度募集和随后单核细胞介导的心功能障碍所必需的。通过利用针对ACE2/Ang1-7/MASR轴的每个成员的敲除和转基因动物，我们将回答定义ACE2轴如何管理单核细胞募集以及改变的募集如何影响梗塞愈合的重要机制问题。这些问题的答案可能对缺血性心脏病的治疗具有广泛的临床意义。

DESCRIPTION (provided by applicant): The goal of this proposal is to develop the principal investigator (PI) into an independent physician- scientist in the field of cardiovascular research. The PI has already undergone both intensive PhD training in the basic science field of immunology and significant additional training in cardiovascular research, both basic science and translational in nature. The PI has completed clinical training in internal medicine and is currently completing the final year of cardiology subspecialty training. The following 5-year career development plan will provide further refinement and training for the PI in order to gain research independence at the conclusion of the award. Dr. Douglas Mann, Chief of Cardiology at Washington University, will mentor the PI. Dr. Mann is a recognized leader in myocardial inflammation and has a tremendous breadth of experience, from defining the role of pro-inflammatory cytokines in heart failure to taking that knowledge and spearheading a clinical trial based on his results. As such, he serves as a perfect example of a successful physician-scientist that is able to translate basic science research into the clinical arena. The PI will tak advantage of this mentorship and the enormous basic science and clinical resources available at Washington University, one of the nation's premier academic institutions, in order to define a new area of clinically relevant basic science research. Myocardial infarction (MI) is a leading cause of morbidity and mortality in the United States and our understanding of the underlying mechanisms remains incomplete. Monocytes are the dominant cell type infiltrating the myocardium in the first week following MI. Unfortunately, little is known about the regulatory factors governing monocyte recruitment despite the fact that excessive recruitment leads to impaired infarct healing. Recent evidence suggests that pathological activation of angiotensin II (AngII) is directly involved in monocyte recruitment following ischemic injury. Angiotensin converting enzyme 2 (ACE2) is a critical endogenous AngII counter-regulator and acts not only to degrade AngII, but produces Ang1-7, a biologically active peptide that binds the Mas receptor (MasR). Enhancing the activity of any component of the ACE2 / Ang1-7 / MasR axis limits myocardial ischemic injury, however the interplay between the ACE2 axis and monocyte recruitment has not been assessed. We hypothesize that a monocyte-localized ACE2 / Ang1-7 / MasR axis exists, and is required to prevent both excessive monocyte recruitment and subsequent monocyte-mediated cardiac dysfunction following myocardial ischemia. By utilizing knockout and transgenic animals that target each member of the ACE2 / Ang1-7 / MasR axis, we will answer important mechanistic questions that define how the ACE2 axis governs monocyte recruitment and how altered recruitment impacts infarct healing. The answers to these questions may have broad clinical implications to the treatment of ischemic heart disease.