权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结/摘要心血管疾病和心力衰竭在退伍军人群体中非常普遍。心脏移植仍然是患有终末期心力衰竭的患者的优选疗法。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也可以增强引发移植物排斥的适应性免疫反应。目前心脏移植术后原发性移植物功能障碍的治疗方法和处理大多数患者都是支持的。我们的实验室开发了活体成像平台，使我们能够真实的观察白细胞渗入小鼠心脏移植物的情况。通过这些方法，我们已经发现了细胞和分子的线索，调节贩运的中性粒细胞和单核细胞，已知介导组织损伤的先天免疫细胞，移植的心脏我们的发现提出了一个有趣的前景，即靶向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，移植在上一个资助期间，我们发现铁性下垂，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。我们已经报道了移植物内皮细胞和组织驻留的CCR 2+巨噬细胞起关键作用，在驱动中性粒细胞向移植心脏的募集中的互补作用。现在我们有产生的初步数据显示，额外的供体免疫细胞群体和信号传导通路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，新的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，将确定供体的作用，非经典单核细胞（Aim 1）和TREM-1/3信号传导（Aim 2）在促进炎症反应中的作用缺血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这些疗法将改善心脏移植受者和患有心脏病的患者的结果。心肌缺血再灌注损伤等。