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

剖析供体 CCR2-巨噬细胞在心脏移植后急性细胞排斥过程中的作用

• 批准号: 10449753
• 负责人: Benjamin J Kopecky
• 金额: $ 15.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449753
• 关键词: Acute; Adult; Advisory Committees; Allogenic; Allografting; Antigen Presentation; Antigen-Presenting Cells; Award; Bioinformatics; Biological Assay; Biology; Cardiology; Cardiovascular system; Cause of Death; Cells; Clinical; Development; Development Plans; Doctor of Philosophy; Donor person; Embryo; Fellowship; Flow Cytometry; Genetic Transcription; Goals; Graft Rejection; Heart; Heart Transplantation; Heart failure; Hematopoietic stem cells; Human; Immune; Immune Targeting; Immune system; Immunologics; Immunology; Immunosuppression; Immunosuppressive Agents; Infection; Inflammation; Inflammatory Response; Interferon Gamma Receptor Complex; Interferon Type II; Internal Medicine; Knowledge; Life; Macrophage Activation; Malignant Neoplasms; Measures; Mediating; Medical; Mentors; Morphology; Mus; Myeloid Cells; Outcome; Pathogenesis; Pathway interactions; Patients; Phagocytosis; Physicians; Population; Positioning Attribute; Postdoctoral Fellow; Principal Investigator; Public Health; Research; Risk; Role; Scientist; Senior Scientist; Signal Pathway; Signal Transduction; T-Lymphocyte; Technical Expertise; Testing; Therapeutic; Three-Dimensional Imaging; Training; Transplantation; United States; allograft rejection; base; beta-Chemokines; career; career development; cell type; cellular imaging; chemokine receptor; cost; curative treatments; gamma-Chemokines; imaging study; improved outcome; in vitro Assay; in vivo; infection risk; intravital imaging; laboratory experience; macrophage; monocyte; novel; novel therapeutics; post-transplant; prevent; protective effect; recruit; single-cell RNA sequencing; skills; success; therapeutic target; tissue repair; transplant model

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.

项目摘要 末期心力衰竭是全球死亡的主要原因，使美国超过300亿美元 每年。心脏移植仍然是唯一的治疗疗法，但是当捐助者时，其成功受到威胁 心脏无法正常工作。当前的免疫抑制治疗重点是针对靶向免疫细胞 接受者的心。这些疗法赋予感染和恶性肿瘤的重大风险，仅适度 有效的。靶向供体 - 接种相互作用可能会提供一种新型的治疗途径。 几种不同的免疫细胞类型位于供体心脏中，巨噬细胞包括大多数 髓样细胞。小鼠和人类心脏至少包含两个可以是巨噬细胞的人群 根据C-C趋化因子受体2（CCR2）的表达而区分。 CCR2+巨噬细胞参与 在炎症反应中，CCR2-巨噬细胞促进组织修复。 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。捐助者的耗尽 CCR2-巨噬细胞加速排斥，而供体CCR2+巨噬细胞的耗竭延长同种异体移植 生存。在此提案中，PI将破译供体CCR2-巨噬细胞的机制 通过调节其他免疫细胞种群和信号通路来防止排斥。 该研究奖的科学目标是确定可以利用的新型免疫种群 了解排斥的机制，并可以在治疗上针对改善预后。 到颁奖期结束时，PI将了解捐助者CCR2-巨噬细胞如何影响捐助者CCR2+ 巨噬细胞激活以及这种激活是否对于同种异体移植排斥（SA1）是必需的。 PI会 研究CCR2-巨噬细胞是如何激活的，以及同种异体移植是否需要这种激活 保护（SA2）。在完成这些目标时，PI将获得流式细胞仪的技术专业知识 成像，散装和单细胞RNA测序，抗原表现，吞噬作用和同种异体反应性测定。 该提议的职业发展目标是将PI发展成为独立的医师科学家 心血管研究领域。 PI先前已经获得了生物学的博士学位培训，并获得了 在他的博士后研究金期间，基本和转化心血管研究的额外培训。 pi 已经完成了内科，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 心脏研究中的免疫学和生物信息学和持续的实验室培训的正式培训 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 由高级科学家组成，他们是免疫学，移植，细胞成像的专家 生物信息学和职业发展。在此奖励期结束时，PI将获得 成为独立和成功的医师科学家所必需的技能。