Long Pentraxin-3 genomics and outcomes after lung transplantation

描述（由申请人提供）：本研究的主要目的是：1)评估肺系统和局部长链pentaxin -3 （PTX3）遗传变异对肺移植术后原发性移植物功能障碍（PGD）发生的差异影响；2)确定PTX3基因表达、蛋白产生、3)检验PTX3基因变异和早期PTX3产生对闭塞性细支气管炎（BOS）或慢性同种异体移植排斥反应的影响；4)为申请人提供技能、知识和经验，使其成为一名以患者为导向的临床研究的独立研究者。PGD在肺移植后很常见，影响到所有受者的30%，并以延长住院时间和机械通气、身体和肺功能差、早期死亡和BOS风险增加的形式导致发病率增加。PGD可能主要由同种异体移植物植入时严重的缺血再灌注损伤引起。先天免疫反应可能在这种情况下上调，然而，它们的机制作用以及全身和肺特异性反应之间的重要差异仍然知之甚少。我们发表的两项研究表明，PTX3血浆水平升高和PTX3基因的常见变异与PGD风险增加有关。然而，这些关联的机制尚不清楚。初步证据表明，基因表达增加和补体激活在这一关系中起着不可或缺的作用。本建议利用宾夕法尼亚大学现有的基础设施，建立一个表型良好的队列，研究PTX3、PGD和BOS的“基因-功能”关联机制。这项前瞻性队列研究将用于评估PTX3循环单核细胞和肺巨噬细胞基因表达、PTX3蛋白浓度和补体激活作为介质在肺移植后暴露、PTX3基因型和结局PGD之间的因果通路中的作用。通过严格的培训计划，包括高级统计分析和遗传流行病学的教学，知名临床研究者的指导，以及深入的研究经验，申请人将获得队列设计和开发，分子实验室技术，因果途径和纵向数据分析以及肺移植结果流行病学的技能。为了确保申请人在研究、出版和职业发展方面达到所有标准，他将与他的主要导师和他的多学科导师团队定期会面。除了他的导师，候选人的环境将提供容易的协作，可访问的统计数据库支持服务，以及众多的核心实验室服务，以促进他的研究和培训目标。本提案将使申请人在肺移植医学领域做出重大贡献，发展成

DESCRIPTION (provided by applicant): The broad objectives of this proposal are to 1) evaluate the differential impact of long pentraxin-3 (PTX3) genetic variation systemically and locally in the lung on the development of primary graft dysfunction (PGD) after lung transplant~ 2) determine the impact of PTX3 gene expression, protein production, and complement activation on the development of PGD using causal mediator analysis~ 3) examine the effect of PTX3 genetic variation and early PTX3 production on the development of bronchiolitis obliterans (BOS), or chronic allograft rejection~ and 4) provide the applicant with the skills, knowledge, and experience required to become an independent investigator in patient oriented clinical research. PGD is common after lung transplantation, affecting up to 30% of all recipients, and leads to increased morbidity in the form of prolonged hospitalization and mechanical ventilation and poor physical and lung function, early death, and increased risk of BOS. PGD likely results primarily from severe ischemia-reperfusion injury at the time of allograft implantation. Innate immune responses are likely upregulated in this setting~ however, their mechanistic role and important differences between systemic and lung-specific responses remain poorly understood. We have published two studies demonstrating that both increased PTX3 plasma levels and common variants in the PTX3 gene are associated with increased risk of PGD. However, the mechanism for these associations is unclear. Preliminary evidence indicates that increased gene expression and complement activation play integral roles in this relationship. This proposal leverages existing infrastructure at the University of Pennsylvania to develop a well- phenotyped cohort to study the "genes- to-function" mechanism of association for PTX3 and PGD and BOS. This prospective cohort study will be used to evaluate the role played by PTX3 circulating monocyte and pulmonary macrophage gene expression, PTX3 protein concentrations, and complement activation as mediators in the causal pathway between the exposure, PTX3 genotype, and the outcome, PGD after lung transplantation. Through a rigorous training plan involving didactics in advanced statistical analysis and genetic epidemiology, mentoring from established clinical investigators, and in-depth research experience, the applicant will gain skills in cohort design and development, molecular laboratory techniques, causal pathway and longitudinal data analysis, and lung transplant outcomes epidemiology. In order to ensure the applicant reaches all benchmarks in research, publication and career development, he will have regular meetings with his primary mentor and his multidisciplinary mentorship team. In addition to his mentors, the candidate's environment will provide easy collaboration, accessible statistical database support services, and numerous core laboratory services to facilitate his research and training goals. This proposal will allow th applicant to make significant contributions to the field of lung transplant medicine, develop into an independent clinical investigator and prepare him for successful future R01-funded projects directed at the development of therapeutics for PGD tailored to innate immune genetic risk factors.