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

ACE2 轴对单核细胞募集至缺血心肌的调节

• 批准号: 8450766
• 负责人: Slava Epelman
• 金额: $ 11.32万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450766
• 关键词: Adoptive Transfer; Angiotensin II; Animals; Area; Award; Basic Science; Binding; Biology; Bone Marrow; Cardiac; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cells; Chemotaxis; Chimera organism; Clinical; Clinical Trials; Coronary Arteriosclerosis; Data; Development; Development Plans; Doctor of Philosophy; Exposure to; Fibrosis; Figs - dietary; Flow Cytometry; Functional disorder; Goals; Healed; Heart failure; Hematopoietic; Immune; Immunology; In Vitro; Individual; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Injury; Institution; Internal Medicine; Ischemia; Knowledge; Lead; Left Ventricular Dysfunction; Left Ventricular Function; Mediating; Mediator of activation protein; Medical; Mentors; Mentorship; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nature; Pathway interactions; Patients; Peptides; Peptidyl-Dipeptidase A; Peripheral; Physicians; Play; Population; Principal Investigator; Process; Public Health; Receptor Activation; Regulation; Regulatory Pathway; Renin-Angiotensin System; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Resources; Role; Scientist; Signal Transduction; Supplementation; Surface; Testing; Therapeutic; Time; Tissues; Training; Transgenic Animals; Translating; United States; Universities; Washington; Wound Healing; angiogenesis; autocrine; base; career development; cell type; clinically relevant; cytokine; experience; healing; improved; in vivo; inhibitor/antagonist; knockout animal; macrophage; member; monocyte; mortality; novel therapeutic intervention; novel therapeutics; prevent; receptor; receptor expression; research study; success; trafficking

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.

描述（由申请人提供）：本提案的目标是将首席研究员（PI）培养成为心血管研究领域的独立医师科学家。 PI 已经接受了免疫学基础科学领域的强化博士培训，以及心血管研究（基础科学和转化性质）的大量额外培训。 PI 已完成内科临床培训，目前正在完成心脏病学亚专业培训的最后一年。接下来的5年职业发展计划将为PI提供进一步的完善和培训，以便在获奖时获得研究独立性。华盛顿大学心脏病学主任 Douglas Mann 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领导一项临床试验。因此，他是一位成功的医师科学家的完美典范，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。 心肌梗塞（MI）是美国发病和死亡的主要原因，我们对其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节因素知之甚少。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。血管紧张素转换酶 2 (ACE2) 是一种重要的内源性 AngII 反调节剂，不仅能降解 AngII，还能产生 Ang1-7，这是一种与 Mas 受体 (MasR) 结合的生物活性肽。增强 ACE2/Ang1-7/MasR 轴任何成分的活性可限制心肌缺血性损伤，但 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，并且是防止心肌缺血后单核细胞过度募集和随后的单核细胞介导的心脏功能障碍所必需的。通过利用针对 ACE2 / Ang1-7 / MasR 轴每个成员的敲除和转基因动物，我们将回答重要的机制问题，这些问题定义了 ACE2 轴如何控制单核细胞募集以及募集改变如何影响梗塞愈合。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。