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

描述（由申请人提供）：本提案的目标是将主要研究者（PI）培养为心血管研究领域的独立医生-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，包括基础科学和转化性质。PI已完成内科临床培训，目前正在完成心脏病学专科培训的最后一年。以下5年职业发展计划将为PI提供进一步的完善和培训，以便在获奖结束时获得研究独立性。华盛顿大学心脏病学主任道格拉斯曼博士将指导PI。Mann博士是心肌炎症领域公认的领导者，拥有丰富的经验，从定义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，他是一个成功的医生，科学家，能够将基础科学研究转化为临床竞技场的完美例子。PI将利用这种指导以及华盛顿大学（美国首屈一指的学术机构之一）提供的大量基础科学和临床资源，以确定临床相关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，我们对潜在机制的理解仍然不完整。单核细胞是MI后第一周浸润心肌的主要细胞类型。不幸的是，尽管事实上，过度募集导致受损的梗死愈合，但对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）的病理激活直接参与缺血性损伤后单核细胞的募集。血管紧张素转化酶2（ACE 2）是一种重要的内源性AngII反调节因子，不仅降解AngII，而且产生Ang 1 -7，一种结合Mas受体（MasR）的生物活性肽。增强ACE 2/Ang 1 -7 / MasR轴的任何组分的活性限制心肌缺血性损伤，然而ACE 2轴和单核细胞募集之间的相互作用尚未评估。我们假设单核细胞定位ACE 2/Ang 1 -7 / MasR轴存在，并且需要防止过度单核细胞募集和随后的心肌缺血后单核细胞介导的心功能障碍。通过利用基因敲除和转基因动物靶向ACE 2/Ang 1 -7 / MasR轴的每一个成员，我们将回答重要的机制问题，定义ACE 2轴如何管理单核细胞的招聘和如何改变招聘影响梗死愈合。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。 公共卫生相关性：这一职业发展建议有两个重要组成部分，将有利于公共卫生。第一个是将主要研究者发展成为一名医生-科学家，这是一名受过独特训练的医生， 患者，确定我们的医学知识的关键差距，并随后研究新的治疗方案。第二个是对一种新发现的能够预防心脏病发作后免疫细胞介导的损伤的途径的进一步表征，这可能为那些患有冠状动脉疾病的人开辟一条新的治疗途径。

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. PUBLIC HEALTH RELEVANCE: This career development proposal has two important components that will benefit public health. The first is the development of the principle investigator into a physician-scientist, which is a uniquely trained medical doctor who by treating patients, identifies critical gaps in our medical knowledge and subsequently investigates new treatment options. The second is the further characterization of a newly identified pathway that is able to prevent immune cell-mediated damage following heart attacks, potentially opening a novel therapeutic avenue for those who suffer from coronary artery disease.