The Clinical and Molecular Impacts of Lung Primary Graft Dysfunction

然而，肺移植对于部分终末期肺部疾病患者来说是一个重要的治疗选择。 患者的结果落后于其他固体器官移植。主要的早期并发症，初级移植物 功能障碍(PGD)，是指移植后3天内发生的急性肺损伤。严重的PGD一直是 与慢性肺移植功能障碍(CLAD)或慢性排斥相关，长期的主要限制 肺移植受者的存活率(Ltrs)。然而，流行病学和基本机制之间的联系 严重的PGD到CLAD代表着该领域的重大知识鸿沟。这项多元PI提案旨在建立 PIT、UCSF和JHU之间的NIH肺移植联盟(LTC)临床中心(CC)调查 重症PGD对急性细胞排斥反应(ACR)和移植物细菌的流行病学和分子影响 感染，这两个因素都是外衣的危险因素，以及一年的肺功能。这项提案考验着 假设PGD启动缺氧和炎症循环，从而驱动ACR、感染和受损的肺 功能。使用批量RNA测序，我们将使用呼吸道刷子样本来评估远端呼吸道转录组 在移植后第一年的3个时间点获得，以确定通过哪些分子途径 严重的PGD会影响呼吸道炎症和肺功能。梅洛博士将执导《目标1号》 确定重度PGD 3级是否是FEV1峰值降低、ACR和同种异体移植物增加的危险因素 第一年的细菌感染。格陵兰博士将执导Aim 2，这将决定严重的PGD是否 与预测肺功能和感染的呼吸道低氧基因信号有关- 年。麦克代尔博士将执导AIM 3，它将确定严重的PGD是否与分子有关 1型炎症和相关ACR的证据。多个PI有很强的协作历史 结合ltrs临床表型、移植免疫学、rnseq分析方面的协同专业知识。 以及对该项目的成功至关重要的生物统计学/生物信息学。每个CC站点都有一个既定的研究 拥有成熟的肺移植登记和生物库的计划，包括呼吸道刷子和经验丰富的 研究协调员、教师和人员，以推进本研究和其他LTC项目的目标。这 LTC CC计划书非常适合解决上述关键知识差距，并带来 一流的能力，以提高LTC的生产率。这一项目的成功将推动流行病学的发展 以及对严重的PGD如何导致肺功能峰值以及缺氧和1型免疫的机械洞察力 移植后第一年呼吸道转录组的反应。总之，这个LTC CC项目将 描绘新的生物标志物和关键的靶向途径，将有助于诊断、治疗和 未来潜在的干预研究，以预防移植后并发症和促进翻译 肺移植科学。

Lung Transplantation is a vital therapeutic option for select individuals with end-stage lung disease, however patient outcomes lag those for other solid organ transplants. The major early complication, primary graft dysfunction (PGD), refers to acute lung injury occurring in the first 3-days posttransplant. Severe PGD has been associated with chronic lung allograft dysfunction (CLAD) or chronic rejection, the major limitation to long-term survival among lung transplant recipients (LTRs). However, the epidemiologic and basic mechanisms that link severe PGD to CLAD represent a significant knowledge gap in the field. This multi-PI proposal seeks to establish an NIH Lung Transplant Consortium (LTC) Clinical Center (CC) between Pitt, UCSF and JHU to investigate the epidemiologic and molecular impacts of severe PGD on acute cellular rejection (ACR) and allograft bacterial infections, which are both risk factors for CLAD, along with one-year pulmonary function. This proposal tests the hypothesis that PGD initiates a cycle of hypoxia and inflammation that drives ACR, infection, and impaired lung function. Using bulk RNA sequencing, we will assess the distal airway transcriptome with airway brush samples obtained at 3 time points during the first-year post transplant, to determine the molecular pathways by which severe PGD impacts airway inflammation and pulmonary function. Dr. Merlo will direct Aim 1, which will determine whether severe PGD grade 3 is a risk-factor for reduced peak FEV1, and increased ACR and allograft bacterial infections in the first-year. Dr. Greenland will direct Aim 2, which will determine whether severe PGD is associated with an airway hypoxia gene signature that predicts pulmonary function and infections in the first- year. Dr. McDyer will direct Aim 3, which will determine whether severe PGD is associated with molecular evidence of Type-1 inflammation and associated ACR. The multi-PIs have a strong history of collaboration together, with synergistic expertise in clinical phenotyping of LTRs, transplant immunology, RNAseq analyses and biostatistics/bioinformatics critical for the success of this project. Each CC site has an established research program with mature lung transplant registries and biorepositories that include airway brushes and experienced research coordinators, faculty, and personnel to advance the aims of this study and other LTC projects. This LTC CC proposal is ideally suited to address both the key knowledge gaps identified above and bring state-of- the-art capabilities to enhance the productivity of the LTC. Success in this project will advance the epidemiologic and mechanistic insights into how severe PGD drives peak pulmonary function, and hypoxic and Type-1 immune responses in the airway transcriptome during the first-year posttransplant. Together, this LTC CC project will delineate novel biomarkers and key targetable pathways that will contribute to the diagnoses, treatment, and potential future interventional studies to prevent post-transplant complications and advance the translational science of lung transplant.