The Role of Family with Sequence Similarity 3D (FAM3D) in Cardioprotection and Inflammation after Myocardial Infarction

序列相似性 3D 家族 (FAM3D) 在心肌梗死后的心脏保护和炎症中的作用

• 批准号: 10080365
• 负责人: James Rhee
• 金额: $ 17.28万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080365
• 关键词: 3-Dimensional; Acute; Acute myocardial infarction; Address; Advisory Committees; Anesthesia procedures; Animal Model; Anti-Inflammatory Agents; Apoptosis; Attenuated; Binding; Cardiac; Cardiac Myocytes; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Separation; Cell Survival; Cells; Characteristics; Chronic; Clinical; Clinical Trials; Collaborations; Complex; Congenic Mice; Critical Care; Data; Development; Development Plans; Doctor of Medicine; Doctor of Philosophy; Echocardiography; Environment; Equilibrium; Event; Faculty; Family; Fibrosis; Flow Cytometry; Gene Expression Profile; General Hospitals; Health Promotion; Heart; Heart Diseases; Heart Injuries; Heart failure; Histologic; Homeostasis; Hypertrophy; Image; Immune; Impairment; Infarction; Inflammation; Injury; Investigation; Leadership; Left Ventricular Function; Leukocyte Trafficking; Leukocytes; Link; Massachusetts; Measures; Mediating; Medicine; Mentors; Mentorship; Modeling; Molecular; Molecular Analysis; Molecular and Cellular Biology; Morbidity - disease rate; Mouse Strains; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocarditis; Myocardium; Organ; PTPRC gene; Pathway interactions; Patients; Perfusion; Plasma; Plasma Proteins; Play; Population; Positioning Attribute; Principal Investigator; Process; Proteins; Proteomics; Recombinant Proteins; Recombinants; Recovery; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Research Proposals; Risk; Role; Sampling; Scientist; Sorting - Cell Movement; Spleen; Splenocyte; Stress; Structure; System; Systems Biology; Testing; Time; Tissues; Troponin; Tweens; United States; Validation; Vascular Endothelium; Viral; aptamer; base; biomarker discovery; biomarker validation; cardioprotection; cardiovascular health; career development; cell injury; cell type; chemokine; cytokine; experience; fMet-Leu-Phe receptor; gain of function; healing; heart function; imaging program; immune activation; immunoregulation; improved; in vivo; insight; instructor; ischemic injury; loss of function; medical schools; member; mid-career faculty; monocyte; mortality; myocardial injury; neutralizing antibody; neutrophil; novel; novel therapeutics; overexpression; preservation; prevent; professor; programs; recruit; response

PROJECT SUMMARY / ABSTRACT: This research proposal outlines a 5-year career development plan for James Rhee, M.D., Ph.D., re- search fellow at the Cardiovascular Research Center at Massachusetts General Hospital (MGH) and Instructor in Anesthesia at Harvard Medical School (HMS), to achieve independence as a principal investigator under the mentorship of Anthony Rosenzweig, M.D., Chief of Cardiology at MGH and Professor of Medicine at HMS. Im- portantly, Dr. Rosenzweig has a strong track record of mentoring scientists with over 50 trainees holding aca- demic faculty positions, many in leadership roles. An advisory committee composed of Fumito Ichinose, Pro- fessor at HMS; Jianren Mao, Vice-Chair of Research; and Saumya Das, Associate Professor of Medicine, along with collaboration from Dr. Matthias Nahrendorf (Director of the Mouse Imaging Program, Center for Sys- tems Biology), will lend expertise on models of biomarker discovery and validation, cardiac stress and inflam- mation and imaging, and career development. Dr. Rhee will take full advantage of the world class environment of the Rosenzweig lab and surrounding MGH and Harvard Medical School campuses in addressing the ambi- tious aims of this proposal. This plan allows Dr. Rhee to develop expertise in cardiovascular proteomics and ischemia reperfusion injury that builds upon his lengthy research experiences in cellular and molecular biology and his clinical role in the critical care of high acuity patients. Cardioprotection and effective adaptation or “remodeling” of the heart after injury is a complex process involving cross-talk between cardiomyocytes and many other cell types. A balance between clearing dead or damaged cells and enhancing the viability of surviving cardiac and non-cardiac tissue, such as vascular endo- thelium, is essential for maintaining homeostasis and recovering function. Optimal remodeling of the myocardi- um after injury is largely dependent on appropriate sequential activation of an immune program involving dif- ferent subtypes of leukocytes. The candidate has used plasma samples from “good” and “poor” remodelers after myocardial infarction to identify secreted factors that may limit acute injury and promote healing. Of the more than 1300 circulating proteins profiled, one of the highest scoring candidates, by both statistical signifi- cance and fold change, is the chemokine Family with sequence similarity 3 member D (FAM3D). Presented in this proposal are compelling preliminary data to suggest that splenic FAM3D exerts acute protection, in the form of dramatically reduced infarct size, after ischemia-reperfusion injury through anti-inflammatory mecha- nisms. Dr.Rhee lays out a comprehensive plan to characterize the completely novel cardiovascular impact of this molecule. He will employ robust in vivo gain- and loss-of-function studies to better understand the role of FAM3D. These studies will lead to a better understanding of ischemic injury and the ensuing inflammation, and to new therapeutic insight into how to limit and treat these conditions in the heart and other vital organs.

项目总结/摘要： 本研究提案概述了James Rhee，M.D.的5年职业发展计划，哲学博士、重新表示 马萨诸塞州总医院心血管研究中心的研究员和讲师 在麻醉在哈佛医学院（HMS），以实现独立的主要研究者根据 安东尼·罗森茨威格博士的指导，MGH心脏病学主任和HMS医学教授。我... 重要的是，罗森茨威格博士有指导科学家的良好记录，有50多名学员持有aca， 学院教职，许多人担任领导职务。由一濑文人、Pro. HMS教授; Jianren Mao，研究副主席;和Saumya Das，医学副教授， 沿着与Matthias Nazodorf博士（系统中心小鼠成像项目主任）的合作， tems生物学），将提供生物标志物发现和验证，心脏应激和炎症模型的专业知识， 信息和成像，以及职业发展。李博士将充分利用世界一流的环境 罗森茨威格实验室和周围的MGH和哈佛医学院校园在解决ambi- 这一提议的目的。该计划使Rhee博士能够发展心血管蛋白质组学方面的专业知识， 缺血再灌注损伤，建立在他在细胞和分子生物学的长期研究经验 以及他在重症监护中的临床作用。 损伤后心脏的保护和有效适应或“重塑”是一个复杂的过程 涉及心肌细胞和许多其他细胞类型之间的串扰。在清算死亡或 损伤的细胞，并增强存活的心脏和非心脏组织，如血管内膜， Thorax是维持体内平衡和恢复功能所必需的。最佳的心肌重塑- 损伤后的免疫系统在很大程度上依赖于免疫程序的适当顺序激活， 白细胞的不同亚型。候选人已经使用了来自“好”和“差”重塑者的血浆样本 以确定可能限制急性损伤和促进愈合的分泌因子。的 超过1300种循环蛋白质，是得分最高的候选者之一，通过两种统计学显著性， 趋化因子FAM 3D是具有序列相似性的趋化因子家族3成员D（FAM 3D）。提出 这一提议是令人信服的初步数据，表明脾FAM 3D发挥急性保护作用，在 缺血再灌注损伤后，通过抗炎机制， nisms。Rhee博士制定了一个全面的计划来描述完全新颖的心血管影响， 这个分子。他将采用强有力的体内功能获得和丧失研究，以更好地了解 FAM 3D。这些研究将有助于更好地了解缺血性损伤和随之而来的炎症， 以及如何限制和治疗心脏和其他重要器官中的这些疾病的新的治疗见解。