Dissecting the Role of Donor CCR2- Macrophages During Acute Cellular Rejection After Heart Transplantation

项目摘要 终末期心力衰竭是全球死亡的主要原因，在美国花费超过300亿美元 每年。心脏移植仍然是唯一的治愈性疗法，但当捐赠者 心脏不能正常工作。目前的免疫抑制治疗集中在靶向免疫细胞， 接受者的心这些疗法具有感染和恶性肿瘤的显著风险， 有效靶向供体-受体相互作用可能提供新的治疗途径。 几种不同的免疫细胞类型存在于供体心脏内，巨噬细胞包含大部分免疫细胞。 骨髓细胞小鼠和人类心脏含有至少两个巨噬细胞群， 基于C-C趋化因子受体2（CCR2）的表达来区分。CCR2+巨噬细胞参与 而CCR2-巨噬细胞促进组织修复。PI已经确定， 供体CCR2-和供体CCR2+巨噬细胞在心脏移植后具有相反的作用。供体耗竭 CCR2-巨噬细胞加速排斥反应，而供体CCR2+巨噬细胞耗竭延长同种异体移植物 生存在该提案中，PI将破译供体CCR2-巨噬细胞 通过调节其他免疫细胞群和信号通路来防止排斥反应。 这项研究奖的科学目标是确定可以利用的新型免疫群体 以了解排斥反应的机制，并可以在治疗上有针对性地改善结果。 在奖励期结束时，PI将了解供体CCR 2-巨噬细胞如何影响供体CCR 2 + 巨噬细胞活化以及这种活化是否是同种异体移植物排斥所必需的（SA1）。pi将 研究CCR2-巨噬细胞如何被激活以及这种激活是否是同种异体移植所必需的 保护（SA2）。在完成这些目标的过程中，PI将获得流式细胞术、活体内 成像、本体和单细胞RNA测序、抗原呈递、吞噬作用和同种异体反应性测定。 本提案的职业发展目标是将PI发展成为一名独立的医生-科学家， 心血管研究领域。PI此前已获得生物学博士培训，并已获得 在博士后研究期间，他接受了基础和转化心血管研究方面的额外培训。的pi 已完成内科、临床心脏病学和晚期心力衰竭的临床培训， 心脏移植奖学金。拟议的5年职业发展计划将为PI提供 免疫学和生物信息学方面的正式培训以及心脏研究方面的持续实验室培训 移植和巨噬细胞生物学。PI将定期与他的导师和咨询委员会会面 由免疫学、移植、细胞成像等领域的资深科学家组成， 生物信息学和职业发展。在此奖励期结束时，PI将获得 成为一名独立和成功的医生科学家所需的技能。

Project Abstract End-stage heart failure is a leading cause of death worldwide and costs the United States over $30 billion annually. Heart transplant remains the only curative therapy but its success is threatened when the donor heart does not work properly. Current immunosuppressive treatments focus on targeting immune cells in the recipient's heart. These therapies confer a significant risk of infections and malignancy and are only modestly effective. Targeting the donor-recipient interaction may provide a novel therapeutic pathway. Several distinct immune cell types reside within the donor heart with macrophages comprising the majority of myeloid cells. The mouse and human heart contain at least two populations of macrophages that can be distinguished based on the expression of C-C chemokine receptor 2 (CCR2). CCR2+ macrophages participate in inflammatory responses whereas CCR2- macrophages promote tissue repair. The PI has established that donor CCR2- and donor CCR2+ macrophages have opposing roles after heart transplant. Depletion of donor CCR2- macrophages accelerates rejection while depletion of donor CCR2+ macrophages prolong allograft survival. In this proposal, the PI will decipher the mechanisms by which donor CCR2- macrophages prevent rejection through their modulation of other immune cell populations and signaling pathways. The scientific goals of this research award are to identify novel immune populations that can be exploited to understand the mechanisms of rejection and can be therapeutically targeted to improve outcomes. By the end of the award period, the PI will understand how donor CCR2- macrophages effect donor CCR2+ macrophage activation and whether this activation is necessary for allograft rejection (SA1). The PI will investigate how CCR2- macrophages become activated and whether this activation is required for allograft protection (SA2). In completing these aims, the PI will gain technical expertise in flow cytometry, intravital imaging, bulk and single cell RNA sequencing, antigen presentation, phagocytosis, and alloreactivity assays. The career development goal of this proposal is to develop the PI into an independent physician-scientist in the field of cardiovascular research. The PI has previously obtained a PhD training in biology and has obtained additional training in basic and translational cardiovascular research during his post-doctoral fellowship. The PI has completed clinical training in Internal Medicine, Clinical Cardiology, and Advanced Heart Failure and Cardiac Transplantation Fellowship. The proposed 5-year career development plan will provide the PI with formal training in immunology and bioinformatics and ongoing laboratory training in the study of cardiac transplantation and macrophage biology. The PI will meet regularly with his mentors and advisory committee which is composed of senior scientists who are experts in immunology, transplantation, cellular imaging, bioinformatics, and career development. At the conclusion of this award period, the PI will have acquired the skills necessary to become an independent and successful physician-scientist.