Leukocyte trafficking in thoracic grafts

项目总结/摘要 心血管疾病和心力衰竭在退伍军人中非常普遍。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 通路调节心脏移植物的白细胞募集。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。

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.