The Clinical and Molecular Impacts of Lung Primary Graft Dysfunction

肺移植是一个重要的治疗选择，为选择个人与终末期肺病，但是， 病人的结果落后于其他实体器官移植。主要的早期并发症， 肺功能障碍（PGD）是指在移植后前3天发生的急性肺损伤。严重的PGD已经 与慢性肺同种异体移植物功能障碍（CLAD）或慢性排斥反应相关， 肺移植受者（LTR）的生存率。然而，流行病学和基本机制， 严重的PGD到CLAD代表了该领域的重大知识差距。这一多PI提案旨在建立 Pitt，UCSF和JHU之间的NIH肺移植联盟（LTC）临床中心（CC）调查 严重PGD对急性细胞排斥反应（ACR）和同种异体移植物细菌感染的流行病学和分子影响 感染，这两者都是CLAD的危险因素，沿着一年的肺功能。该提案测试了 假设PGD启动缺氧和炎症循环，驱动ACR、感染和肺损伤 功能使用批量RNA测序，我们将评估气道刷样本的远端气道转录组 在移植后第一年的3个时间点获得，以确定 严重的PGD影响气道炎症和肺功能。Merlo博士将指导Aim 1， 确定重度PGD 3级是否是FEV 1峰值降低、ACR和同种异体移植物增加的风险因素 第一年的细菌感染。格陵兰博士将指导目标2，这将决定是否严重的PGD是 与气道缺氧基因特征相关，该基因特征可预测肺功能和感染， 年McDyer博士将指导目标3，该目标将确定严重的PGD是否与分子水平相关。 1型炎症和相关ACR的证据。多个PI有很强的合作历史 结合LTR临床表型分型、移植免疫学、RNAseq分析等方面的协同专业知识， 和生物统计学/生物信息学对该项目的成功至关重要。每个CC站点都有一个既定的研究 成熟的肺移植登记和生物储存库，包括气道刷和经验丰富的 研究协调员，教师和人员，以推进这项研究和其他LTC项目的目标。这 LTC CC提案非常适合解决上文确定的关键知识差距， 提高LTC的生产力。该项目的成功将推动流行病学 以及严重的PGD如何驱动峰值肺功能的机制见解，以及缺氧和1型免疫 移植后第一年气道转录组的反应。LTC CC项目将 描述新的生物标志物和关键的靶向途径，这将有助于诊断，治疗， 潜在的未来干预性研究，以预防移植后并发症， 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.