Leukocyte trafficking in thoracic grafts

胸廓移植物中的白细胞贩运

基本信息

批准号：
10609798
负责人：
Daniel Kreisel
金额：
--
依托单位：
ST. LOUIS VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10609798
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 Endothelium 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 Iron Laboratories Leucocytic infiltrate Leukocyte Trafficking Leukocytes Macrophage Mediating Molecular Mus Myeloid Cells Myocardial Ischemia Myocardial Reperfusion Injury Neutrophil Infiltration Outcome Pathway interactions Patients Pattern Plasma Cells Play Population Positron-Emission Tomography Process Production RNA Reperfusion Injury Reperfusion Therapy Reporting Role Shapes Signal Pathway Signal Transduction Site Specific qualifier value Structure of left gastric vein Surface T-Lymphocyte TLR3 gene TLR4 gene Techniques Testing Time Tissues Transplant Recipients Transplantation Veterans Visualization adaptive immune response chemokine effective therapy extracellular graft dysfunction imaging approach imaging platform improved outcome intravital imaging isoimmunity migration military veteran monocyte neutrophil novel novel therapeutics pharmacologic receptor recruit response single-cell RNA sequencing trafficking two photon microscopy

项目摘要

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.

项目摘要 /摘要在退伍军人人群中，心血管疾病和心力衰竭非常普遍。心脏对于患有末期心力衰竭的患者，移植仍然是一种首选治疗。但是，心脏移植后的结果受到原发性移植功能障碍的不利影响，缺血再灌注损伤的结果。一级移植功能障碍会引起立即组织损坏，还可以增加触发移植物排斥反应的适应性免疫反应。目前，那里心脏移植后没有有效的原发性移植功能障碍的疗法和管理这些患者主要是支持的。我们的实验室已经开发了浸泡成像平台使我们能够实时可视化白细胞浸润到鼠心移植中。通过这些方法我们发现了调节贩运的细胞和分子提示中性粒细胞和单核细胞，固有的免疫细胞，已知会介导组织损伤，进入移植的心。我们的发现提出了针对免疫途径和细胞的有趣前景供体移植物中的种群可以控制心脏之后的初始免疫反应移植。在上一个资金期间，我们发现铁铁作用是一种非细胞死亡的凋亡形式介导心脏移植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居住的CCR2+巨噬细胞的行为至关重要，互补的作用在将中性粒细胞募集到移植的心脏中。现在我们有生成的初步数据表明其他供体免疫细胞群体和信号传导途径调节白细胞募集到心脏移植物。在此提案中，我们将使用最先进的包括插入式两光子显微镜，新正电子发射断层扫描探针的技术，单细胞RNA测序和新型鼠菌株进行研究，以定义供体的作用非古典单核细胞（AIM 1）和TREM-1/3信号传导（AIM 2）促进炎症缺血性心脏移植物再灌注后的反应。我们的研究将为小说奠定基础可以改善心脏移植接受者和患者的疗法由于其他疾病而导致的心肌缺血再灌注损伤。