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.

肺移植是一个重要的治疗选择，选择个人终末期肺病

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。

• DOI: 10.1016/j.jtcvs.2024.01.045
• 发表时间: 2024
• 期刊: The Journal of thoracic and cardiovascular surgery
• 作者: Kalra,Andrew;Ruck,JessicaM;Zhou,AliceL;Akbar,ArmaanF;Shou,BenjaminL;Casillan,AlfredJ;Ha,JinnyS;Merlo,ChristianA;Bush,ErrolL
• 通讯作者: Bush,ErrolL