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主要的死亡原因，给美国造成了超过300亿美元的损失 每年一次。心脏移植仍然是唯一的根治方法，但当捐赠者 心脏不能正常工作。目前的免疫抑制治疗主要集中在靶向免疫细胞上。 接受者的心脏。这些疗法有很大的感染和恶性风险，而且治疗效果不大。 有效。靶向供受者之间的相互作用可能提供一种新的治疗途径。 供者心脏内有几种不同的免疫细胞类型，其中巨噬细胞构成了大部分 髓系细胞。小鼠和人的心脏至少含有两组巨噬细胞，它们可以是 根据C-C趋化因子受体2(CCR2)的表达来区分。CCR2+巨噬细胞参与 在炎症反应中，CCR2-巨噬细胞促进组织修复。公安局已经确定 供体CCR2-和供体CCR2+巨噬细胞在心脏移植后具有相反的作用。供体耗尽 CCR2-巨噬细胞加速排斥反应，供体CCR2+巨噬细胞耗竭延长同种异体移植 生死存亡。在这项提议中，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。 该研究奖的科学目标是确定可以利用的新免疫种群。 了解排斥反应的机制，并可在治疗上有针对性地改善结果。 在获奖期结束时，PI将了解供体CCR2-巨噬细胞如何影响供体CCR2+ 巨噬细胞激活以及这种激活是否是同种异体移植排斥反应所必需的(SA1)。私人侦探将 研究CCR2-巨噬细胞是如何被激活的，以及这种激活是否是同种异体移植所必需的 保护(SA2)。在实现这些目标的过程中，PI将获得Inlive的流式细胞术的技术专长 成像、散装和单细胞RNA测序、抗原呈递、吞噬和同种异体反应性分析。 这项建议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之前曾接受过生物学博士培训，并已获得 在他的博士后研究期间，他还接受了基础和翻译心血管研究方面的额外培训。《少年派》 已完成内科、临床心脏病学和高级心力衰竭的临床培训，并 心脏移植团契。拟议的五年职业发展计划将为专业人员提供 在免疫学和生物信息学方面的正规培训以及在心脏疾病研究方面的持续实验室培训 移植和巨噬细胞生物学。私家侦探将定期与他的导师和咨询委员会会面 它由资深科学家组成，他们是免疫学，移植，细胞成像， 生物信息学和职业发展。在此授权期结束时，PI将获得 成为一名独立和成功的内科科学家所需的技能。

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.