The Clinical and Molecular Impacts of Lung Primary Graft Dysfunction

原发性移植肺功能障碍的临床和分子影响

• 批准号: 10430393
• 负责人: JOHN GREENLAND
• 金额: $ 46.54万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10430393
• 关键词: Acute; Acute Lung Injury; Address; Airway Fibrosis; Allografting; Bacterial Infections; Bioinformatics; Biometry; Bronchiolitis Obliterans; Bronchitis; Cells; Chronic; Clinical; Collaborations; Complication; Data; Development; Diagnosis; Distal; Epidemiology; Epithelial; Epithelial Cells; Event; Faculty; Forced expiratory volume function; Functional disorder; Future; Gene Expression; Genes; Greenland; Human Resources; Hypoxemia; Hypoxia; Immune; Immune Targeting; Immune response; Immunity; Impairment; Individual; Infection; Inflammation; Inflammatory; Injury; Intervention Studies; Knowledge; Lead; Link; Lung; Lung Transplantation; Lung diseases; Lung infections; Lymphocyte; Metagenomics; Microbiology; Molecular; Organ Transplantation; Outcome; Pathogenesis; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Predisposition; Prevention; Process; Productivity; Publishing; Pulmonary Edema; Pulmonary Function Test/Forced Expiratory Volume 1; Recording of previous events; Reperfusion Injury; Research; Respiratory Tract Infections; Risk; Risk Factors; Role; Sampling; Science; Site; Solid; Standardization; Stimulus; Techniques; Testing; Therapeutic; Time; Translational Research; Transplant Recipients; Transplantation; Transplantation Immunology; United States National Institutes of Health; airway epithelium; airway inflammation; biobank; case control; clinical center; clinical phenotype; experience; falls; genetic signature; graft dysfunction; immune activation; injured airway; insight; lung allograft; multidisciplinary; novel; novel marker; post-transplant; predictive signature; prevent; programs; pulmonary function; repaired; respiratory hypoxia; success; transcriptome; transcriptome sequencing; transplant centers; transplant registry

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.

对于精选终末期肺部疾病的人来说，肺移植是至关重要的治疗选择，但是 患者的结果滞后于其他固体器官移植。主要的早期并发症，主要移植物 功能障碍（PGD）是指移植后前三天发生的急性肺损伤。严重的PGD已经 与慢性肺同种异体功能障碍（CLAD）或慢性排斥相关，这是长期的主要限制 肺移植受者（LTRS）之间的存活率。但是，连接的流行病学和基本机制 严重的PGD代表该领域的显着知识差距。该多PI提案旨在建立 PITT，UCSF和JHU之间的NIH肺移植财团（LTC）临床中心（CC）研究 严重PGD对急性细胞排斥（ACR）和同种异体移植细菌的流行病学和分子影响 感染，都是外壳的危险因素，以及一年的肺功能。该建议测试 PGD​​启动缺氧和炎症循环的假设驱动ACR，感染和肺部受损 功能。使用散装RNA测序，我们将使用气道刷样品评估远端气道转录组 在移植后第一年的3个时间点获得，以确定分子途径 严重的PGD会影响气道炎症和肺功能。 Merlo博士将指导AIM 1，这将 确定严重的PGD 3级是否是降低峰值FEV1的风险因素，并增加了ACR和同种异体移植物 第一年的细菌感染。格陵兰博士将指导AIM 2，这将确定严重的PGD是否是 与气道缺氧基因特征相关 年。 McDyer博士将指导AIM 3，这将确定严重的PGD是否与分子有关 1型炎症和相关ACR的证据。多派有很强的合作历史 借助LTRS的临床表型，移植免疫学的协同专业知识，RNASEQ分析了 生物统计学/生物信息学对于该项目的成功至关重要。每个CC网站都有一项既定的研究 具有成熟的肺移植登记处和生物座席的计划，包括气道刷和经验丰富 研究协调员，教师和人员促进了这项研究和其他LTC项目的目标。这 LTC CC提案非常适合解决上述关键知识差距，并带来最新 提高LTC生产率的艺术能力。该项目的成功将推动流行病学 以及关于严重PGD如何驱动峰值肺功能以及低氧和1型免疫的机械洞察力 移植后第一年的气道转录组中的响应。该LTC CC项目将在一起 描绘新型生物标志物和主要目标途径，这些途径将有助于诊断，治疗和 潜在的未来介入研究以防止移植后并发症并推动翻译 肺移植科学。