Lung Transplant donor: prediction, evaluation, and mechanism

肺移植供体：预测、评估和机制

• 批准号: 8609591
• 负责人: EDWARD CANTU
• 金额: $ 16.02万
• 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/8609591
• 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）：主要的移植功能障碍（PGD）是肺移植后发病和死亡率的最常见原因。最近的数据表明，一些特定途径参与急性肺损伤模型和移植后PGD。对这些特定途径的更好理解将为PGD发病机理提供机械线索，并可能刺激对新型治疗途径的研究。此外，识别PGD的特定，个性化的风险因素可能允许将来的个性化治疗。我们的初步数据表明，与对照组相比，在确定为PGD的最大折叠差异的顶部基因中，ANGPT2是血管炎症/渗透性的关键介质表明，供体的采购前供体增长了7倍，进一步增加了10倍后再生后再灌注。鉴于在收获前我们的移植队列中ANGPT2基因表达的上调，尽管需要进一步表征的是正常的生理测量值，但肺似乎仍未受到损伤。我们的研究线的长期目标是了解人类肺移植中PGD的机制，以确定识别有风险捐助者的策略，防止接受者死亡 并有可能通过更好的供体选择和使用离体肺灌注（EVLP）策略来扩展供体池。我们的方法是在供体肺活检中使用基因表达来预测PGD，并检查与移植供体PGD有关的特定炎症，先天免疫和血管通透性途径，以及放置在EVLP上的不可转移的供体。中心假设是，可以通过基因表达方法评估供体肺中发生的肺损伤，以确定PGD风险，确定本来可以被丢弃的“低风险”器官，并了解EVLP上PGD的常见机制和恢复。该项目的完成将为候选人提供高级培训和队列研究设计和行为的重要经验；在基因，表达和途径水平上调整遗传分析；并应用高级生物信息学和计算技术进行途径分析和风险预测。候选人组建了一个丰富的指导委员会，该委员会涵盖了以患者为导向的研究，分子和遗传流行病学，基因组学，生物信息学和分子生物学方面的专业知识。此外，他还通过临床流行病学硕士学位利用宾夕法尼亚州的杰出教育机会。该提案绘制了一个明确的计划，以使候选人成为以患者为导向的转化研究中的独立临床研究者。