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）：原发性移植物功能障碍（PGD）是肺移植后发病和死亡的最常见原因。最近的数据表明，在急性肺损伤模型和移植后PGD中有一些特定的通路参与。更好地了解这些特定的途径将提供机制线索PGD的发病机制，并可能刺激新的治疗途径的调查。此外，识别PGD的特定、个体化风险因素可能有助于未来的个性化治疗。我们的初步数据表明，在被鉴定为与对照相比在PGD中具有最大倍数差异的前几个基因中，血管炎症/渗透性的关键介质ANGPT 2在供体获取前显示出7倍的增加，其在再灌注后进一步增加了另外的10倍。鉴于在我们的移植队列中ANGPT 2基因表达在收获前上调，尽管生理测量正常，但似乎存在对肺的不可测量的损伤，这需要进一步表征。本研究的长期目标是了解人肺移植中PGD的机制，以确定识别风险供体，防止受体死亡的策略 并通过更好的供体选择和使用离体肺灌注（EVLP）策略潜在地扩大供体库。我们的方法是使用供体肺活检中的基因表达来预测PGD，并检查移植供体和置于EVLP上的不可移植供体的PGD中涉及的特异性炎症、先天免疫和血管通透性途径。中心假设是，可以通过基因表达方法评估再灌注前供体肺中发生的肺损伤，以确定PGD风险，鉴定可以移植的已被丢弃的“低风险”器官，并了解PGD和EVLP恢复的常见机制。该项目的完成将为候选人提供队列研究设计和实施方面的高级培训和关键经验;在基因，表达和途径水平上定制遗传分析;并将先进的生物信息学和计算技术应用于途径分析和风险预测。候选人已经组建了一个丰富的指导委员会，涵盖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大学出色的教育机会。该提案描绘了一个明确的计划，允许候选人成为以患者为导向的转化研究的独立临床研究者。