Lung Transplant donor: prediction, evaluation, and mechanism

描述(申请人提供)：原发移植物功能障碍(PGD)是肺移植后发病率和死亡率的最常见原因。最近的数据表明，一些特定的途径参与了急性肺损伤模型和移植后的PGD。更好地了解这些特定的通路将为PGD的发病机制提供线索，并有可能刺激对新的治疗途径的研究。此外，识别特定的、个性化的PGD危险因素可能会使未来的个体化治疗成为可能。我们的初步数据显示，在与对照组相比PGD差异最大的顶级基因中，血管炎症/通透性的关键介质ANGPT2在供者采购前增加了7倍，这进一步增加了再灌注后的10倍。鉴于我们的移植队列中ANGPT2基因的表达在收获前上调，尽管正常的生理测量需要进一步表征，但似乎对肺的损伤是不可测量的。我们这一系列研究的长期目标是了解PGD在人类肺移植中的机制，以便确定策略，识别处于危险中的供者，防止受者死亡。 通过更好的供者选择和体外肺灌流(EVLP)策略的使用，有可能扩大供者池。我们的方法是利用供体肺活检组织中的基因表达来预测PGD，并检测移植供体和不能移植供体放置EVLP后参与PGD的特异性炎症、先天免疫和血管通透性途径。核心假设是，供体肺在再灌注前发生的肺损伤可以通过基因表达方法进行评估，以确定PGD的风险，识别可以移植的“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以下方面的高级培训和关键经验：队列研究设计和实施；基因、表达和途径一级的基因分析；以及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。这位候选人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方面的专业知识。此外，他正在利用宾夕法尼亚大学优秀的教育机会，通过临床流行病学硕士学位。该提案制定了一个明确的计划，允许候选人在面向患者的转化研究中成为独立的临床研究员。

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.