Lung Transplant donor: prediction, evaluation, and mechanism

肺移植供体：预测、评估和机制

基本信息

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
项目类别：
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

项目摘要

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。最近的数据表明一些特定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，并有可能刺激新治疗途径的研究。此外，识别特定的、个体化的 PGD 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，与对照相比，在 PGD 中具有最大倍数差异的顶级基因中，ANGPT2（血管炎症/通透性的关键介质）在供体预采购中表现出 7 倍的增加，进一步增加了 10 倍再灌注后。鉴于我们的移植队列在收获前 ANGPT2 基因表达上调，尽管生理测量正常，但肺部似乎存在无法测量的损伤，这需要进一步表征。我们研究的长期目标是了解人肺移植中 PGD 的机制，以便确定识别有风险的供者、防止受者死亡的策略通过更好的供体选择和使用离体肺灌注（EVLP）策略，有可能扩大供体库。我们的方法是利用供体肺活检中的基因表达来预测 PGD，并检查移植供体和接受 EVLP 的不可移植供体的 PGD 中涉及的特定炎症、先天免疫和血管通透性途径。中心假设是，再灌注前发生在供体肺中的肺损伤可以通过基因表达方法进行评估，以确定 PGD 风险，识别可能被丢弃但可以移植的“低风险”器官，并了解 PGD 和移植的常见机制。 EVLP 上的恢复。完成该项目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；并应用先进的生物信息学和计算技术进行路径分析和风险预测。该候选人组建了一个内容丰富的指导委员会，涵盖以患者为中心的研究、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，他还利用宾夕法尼亚大学出色的教育机会，攻读临床流行病学硕士学位。该提案制定了一个明确的计划，使候选人能够成为以患者为导向的转化研究中的独立临床研究者。