Lung Transplant donor: prediction, evaluation, and mechanism

肺移植供体：预测、评估和机制

• 批准号: 8424616
• 负责人: EDWARD CANTU
• 金额: $ 16.06万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424616
• 关键词: ANGPT2 gene; Acute Lung Injury; Affect; Allografting; American; Angiopoietin-2; Bioinformatics; Biopsy; Biopsy Specimen; Cause of Death; Cessation of life; Chronic lung disease; Classification; Clinical; Clinical Investigator; Clinical assessments; Cohort Studies; Computational Technique; Data; Development; Discrimination; Donor Selection; Donor person; Evaluation; Functional disorder; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genomics; Harvest; Hospitals; Hour; Human; Inflammatory; Injury; Investigation; Knowledge; Label; Lead; Lung; Lung Transplantation; Lung diseases; Maps; Measurement; Measures; Mediator of activation protein; Mentors; Messenger RNA; Methodology; Methods; Metric; Modeling; Molecular; Molecular Biology; Molecular Epidemiology; Molecular Profiling; Morbidity - disease rate; Natural Immunity; Organ; Organ Donor; Organ Transplantation; Outcome; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Pattern; Perfusion; Perioperative; Permeability; Physiological; Population; Postoperative Period; Predisposition; Pulmonary Vascular Resistance; Recovery; Regulator Genes; Rehabilitation therapy; Reperfusion Injury; Reperfusion Therapy; Research; Research Design; Research Personnel; Research Training; Risk; Risk Factors; Rosa; Selection Criteria; Staging; Technology; Testing; Therapeutic; Time; Tissue Donors; Tissues; Training; Transcript; Translational Research; Transplant Recipients; Transplantation; Up-Regulation; Validation; Variant; Vascular Permeabilities; Waiting Lists; Work; base; clinical decision-making; clinical epidemiology; cohort; experience; gene function; genetic analysis; genetic epidemiology; genome-wide; high risk; improved; lung allograft; lung injury; mortality; new technology; novel; novel therapeutics; patient oriented; patient oriented research; prevent; therapeutic target; vascular inflammation

DESCRIPTION (provided by applicant): Primary graft dysfunction (PGD) is the most common cause of morbidity and mortality after lung transplantation. Recent data indicate participation of a few specific pathways in acute lung injury models and post-transplant PGD. A better understanding of these specific pathways would offer mechanistic clues to PGD pathogenesis and potentially stimulate investigation of novel therapeutic avenues. In addition, identification o specific, individualized risk factors for PGD might allow future personalized therapy. Our preliminary data indicate that among the top genes identified as having the largest fold differences in PGD compared to control, ANGPT2 a key mediator of vascular inflammation/ permeability demonstrated a 7-fold increase in donors pre- procurement which further increased an additional 10-fold post reperfusion. Given the up-regulation of ANGPT2 gene expression in our transplant cohort prior to harvest, there appears to be unmeasured injury to the lung despite normal physiologic measurements which needs to be further characterized. The long-term objective of our line of research is to understand the mechanism of PGD in human lung transplantation in order to identify strategies to identify donors at risk, prevent recipient death and potentially expand the donor pool through better donor selection and use of ex vivo lung perfusion (EVLP) strategies. Our approach is to use gene expression in donor lung biopsies to predict PGD, and to examine specific inflammatory, innate immunity and vascular permeability pathways involved in PGD of transplanted donors and untransplantable donors placed on EVLP. The central hypotheses are that lung injury occurring in the donor lung prior to reperfusion can be evaluated by gene expression methods to determine PGD risk, identify "low risk" organs that would have been discarded that can be transplanted, and understand common mechanisms of PGD and recovery on EVLP. Completion of this project will provide the candidate with advanced training and critical experience in cohort study design and conduct; tailoring genetic analysis at the gene, expression and pathway level; and applying advanced bioinformatic and computational techniques for pathways analysis and risk prediction. The candidate has assembled a rich mentoring committee spanning expertise in patient-oriented research, molecular and genetic epidemiology, genomics, bioinformatics, and molecular biology. In addition, he is taking advantage of Penn's outstanding educational opportunities through a Master's in Clinical Epidemiology. The proposal maps a clear plan to allow the candidate to become an independent clinical investigator in patient-oriented translational research.

描述（由申请人提供）：原发性移植物功能障碍（PGD）是肺移植术后最常见的发病和死亡原因。最近的数据表明，一些特定的途径参与急性肺损伤模型和移植后PGD。更好地了解这些特定途径将为PGD发病机制提供机制线索，并有可能刺激新的治疗途径的研究。此外，确定特定的、个体化的PGD风险因素可能会使未来的个性化治疗成为可能。我们的初步数据表明，与对照相比，在PGD差异最大的顶级基因中，ANGPT2（血管炎症/通透性的关键介质）在供体获取前增加了7倍，在再灌注后进一步增加了10倍。考虑到我们的移植队列在收获前ANGPT2基因表达上调，尽管正常的生理测量，但似乎存在未测量到的肺损伤，这需要进一步表征。我们研究的长期目标是了解PGD在人肺移植中的机制，以便确定识别有风险的供体的策略，防止受体死亡