Leukocyte trafficking in thoracic grafts

胸廓移植物中的白细胞贩运

• 批准号: 10370119
• 负责人: Daniel Kreisel
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370119
• 关键词: Adhesions; Automobile Driving; CCL2 gene; CCL7 gene; CXCL5 gene; Cardiovascular Diseases; Cell Death; Cells; Cessation of life; Chest; Complex; Cues; Data; Endothelial Cells; Extravasation; Foundations; Funding; Graft Rejection; Grant; Health; Heart; Heart Transplantation; Heart failure; Human; Image; Immune; Immune Targeting; Immune response; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interferon Type I; Interleukin-1; Iron; Laboratories; Leukocyte Trafficking; Leukocytes; Light; Mediating; Molecular; Mus; Myeloid Cells; Myocardial Ischemia; Neutrophil Infiltration; Outcome; Pathway interactions; Patients; Pattern; Pharmacology; Plasma Cells; Play; Population; Positron-Emission Tomography; Process; Production; RNA; Reperfusion Injury; Reperfusion Therapy; Reporting; Role; Shapes; Signal Pathway; Signal Transduction; Site; Structure of left gastric vein; Surface; T-Lymphocyte; TLR3 gene; TLR4 gene; Techniques; Testing; Time; Tissues; Transplant Recipients; Transplantation; Veterans; adaptive immune response; base; chemokine; effective therapy; extracellular; graft dysfunction; imaging approach; imaging platform; improved outcome; intravital imaging; isoimmunity; macrophage; migration; military veteran; monocyte; neutrophil; novel; novel therapeutics; receptor; recruit; response; single-cell RNA sequencing; trafficking; two photon microscopy

Project Summary / Abstract Cardiovascular disease and heart failure are highly prevalent among the veteran population. Cardiac transplantation remains a preferred therapy for patients who suffer from end-stage heart failure. However, outcomes after heart transplantation are adversely impacted by primary graft dysfunction, a consequence of ischemia reperfusion injury. Primary graft dysfunction causes immediate tissue damage and can also augment adaptive immune responses that trigger graft rejection. Currently, there are no effective therapies for primary graft dysfunction after heart transplantation and the management of these patients is mostly supportive. Our laboratory has developed intravital imaging platforms that has allowed us to visualize the infiltration of leukocytes into murine heart grafts in real time. Through these approaches we have uncovered cellular and molecular cues that regulate the trafficking of neutrophils and monocytes, innate immune cells that are known to mediate tissue damage, into transplanted hearts. Our findings raise the intriguing prospect that targeting immune pathways and cell populations within the donor graft can control the initial immune response following heart transplantation. During the previous funding period we have discovered that ferroptosis, a non- apoptotic form of cell death mediates the early inflammatory response after reperfusion of heart grafts. We have reported that graft endothelial cells and tissue-resident CCR2+ macrophages play critical and complementary roles in driving the recruitment of neutrophils to the transplanted heart. Now we have generated preliminary data showing that additional donor immune cell populations and signaling pathways regulate leukocyte recruitment to cardiac grafts. In this proposal, we will use state-of-the-art techniques including intravital two-photon microscopy, new positron emission tomography probes, single cell RNA sequencing and novel murine strains to perform studies that will define the role of donor non-classical monocytes (Aim 1) and TREM-1/3 signaling (Aim 2) in promoting inflammatory responses after reperfusion of ischemic heart grafts. Our studies will lay the foundation for novel therapies that will improve outcomes for heart transplant recipients and patients who suffer from myocardial ischemia reperfusion injury due to other conditions.

项目概要/摘要 心血管疾病和心力衰竭在退伍军人群体中非常普遍。心脏 移植仍然是终末期心力衰竭患者的首选治疗方法。 然而，心脏移植后的结果受到原发性移植物功能障碍的不利影响， 缺血再灌注损伤的后果。原发性移植物功能障碍导致直接组织 损伤，还可以增强引发移植排斥的适应性免疫反应。目前，有 对于心脏移植后原发性移植物功能障碍没有有效的治疗方法和管理 这些患者大多是支持的。我们的实验室开发了活体成像平台 使我们能够实时观察白细胞浸润到小鼠心脏移植物中的情况。通过 通过这些方法，我们发现了调节转运的细胞和分子线索 中性粒细胞和单核细胞，已知可介导组织损伤的先天免疫细胞， 移植的心脏。我们的研究结果提出了一个有趣的前景，即针对免疫途径和细胞 供体移植物内的群体可以控制心脏移植后的初始免疫反应 移植。在之前的资助期间，我们发现铁死亡是一种非 细胞死亡的凋亡形式介导心脏移植物再灌注后的早期炎症反应。 我们报道了移植物内皮细胞和组织驻留 CCR2+ 巨噬细胞发挥着至关重要的作用 在驱动中性粒细胞募集至移植心脏方面发挥互补作用。现在我们有 生成的初步数据显示额外的供体免疫细胞群和信号传导 途径调节白细胞向心脏移植物的募集。在这个提案中，我们将使用最先进的 技术包括活体双光子显微镜、新型正电子发射断层扫描探针、 单细胞 RNA 测序和新的小鼠品系进行研究，以确定供体的作用 非经典单核细胞（目标 1）和 TREM-1/3 信号传导（目标 2）促进炎症 缺血性心脏移植物再灌注后的反应。我们的学习将为小说奠定基础 可以改善心脏移植受者和患有以下疾病的患者的结果的疗法 其他情况引起的心肌缺血再灌注损伤。