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: 10677642
• 负责人: JOHN GREENLAND
• 金额: $ 44.17万
• 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/10677642
• 关键词: Acute; Acute Lung Injury; Address; Airway Fibrosis; Allografting; Bacterial Infections; Bioinformatics; Biological; Biometry; Bronchiolitis Obliterans; Bronchitis; Cells; Chronic; Clinical; Collaborations; Complication; Data; Development; Diagnosis; Distal; Epidemiology; Epithelial Cells; Epithelium; 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; Link; Lung; Lung Transplantation; Lung diseases; Lung infections; Lymphocyte; Metagenomics; 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; 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.

然而，对于特定的终末期肺病患者来说，肺移植是一种重要的治疗选择 患者的结果落后于其他实体器官移植。主要的早期并发症，原发性移植物 功能障碍（PGD）是指移植后前 3 天发生的急性肺损伤。严重的PGD 与慢性肺同种异体移植功能障碍（CLAD）或慢性排斥反应有关，这是长期治疗的主要限制 肺移植受者（LTR）的存活率。然而，将这些因素联系起来的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。该多 PI 提案旨在建立 皮特大学、加州大学旧金山分校和约翰霍普金斯大学之间的 NIH 肺移植联盟 (LTC) 临床中心 (CC) 负责调查 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（两者都是 CLAD 的危险因素）以及一年的肺功能。该提案测试了 假设 PGD 启动缺氧和炎症循环，从而导致 ACR、感染和肺部受损 功能。使用批量 RNA 测序，我们将使用气道刷样本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 博士将指导目标 1，该目标将 确定严重的 PGD 3 级是否是峰值 FEV1 降低、ACR 和同种异体移植物增加的危险因素 第一年细菌感染。 Greenland 博士将指导目标 2，该目标将确定是否需要进行严重的 PGD 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 是否与分子生物学相关。 1 型炎症和相关 ACR 的证据。多个 PI 有着悠久的合作历史 凭借 LTR 临床表型分析、移植免疫学、RNAseq 分析方面的协同专业知识 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 站点都有既定的研究 拥有成熟的肺移植登记处和生物样本库的计划，其中包括气道刷和经验丰富的人员 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 提案非常适合解决上述确定的关键知识差距并带来现状 提高 LTC 生产力的最先进功能。该项目的成功将推动流行病学研究 以及关于严重 PGD 如何驱动肺功能峰值、缺氧和 1 型免疫的机制见解 移植后第一年气道转录组的反应。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，这将有助于诊断、治疗和 未来潜在的干预研究可预防移植后并发症并推进转化 肺移植科学。

项目成果

Bigger pies, bigger slices: Increased hospitalization costs for lung transplantation recipients in the non-donation service area allocation era.

蛋糕越大，切片越大：非捐献服务区分配时代肺移植受者的住院费用增加。

• 发表时间: 2024-03-08
• 作者: Kalra, Andrew;Ruck, Jessica M;Zhou, Alice L;Akbar, Armaan F;Shou, Benjamin L;Casillan, Alfred J;Ha, Jinny S;Merlo, Christian A;Bush, Errol L
• 通讯作者: Bush, Errol L