Long Pentraxin-3 genomics and outcomes after lung transplantation

Long Pentraxin-3 基因组学和肺移植后的结果

• 批准号: 8766367
• 负责人: Joshua M. Diamond
• 金额: $ 13.92万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766367
• 关键词: Accounting; Acute Lung Injury; Address; Affect; Allografting; Alveolar Macrophages; Benchmarking; Biological Response Modifiers; Breathing; Bronchiolitis Obliterans; Cells; Cessation of life; Chronic; Chronic Obstructive Airway Disease; Clinical Investigator; Clinical Research; Clinical Trials; Cohort Studies; Collaborations; Complement; Complement Activation; Cystic Fibrosis; Data; Data Analyses; Databases; Dendritic Cells; Development; Drug Administration Routes; Ensure; Environment; Epidemiologist; Epidemiology; Functional disorder; Funding; Future; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Hamman-Rich syndrome; Health; Hospitalization; Immune; Immune response; Interleukin-1; Intravenous; Knowledge; Laboratories; Lead; Length of Stay; Link; Lung; Lung Transplantation; Lung diseases; Measures; Mechanical ventilation; Mediating; Mediator of activation protein; Mentors; Mentorship; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Natural Immunity; Organ Transplantation; Outcome; PTX3 protein; Pathogenesis; Pathway interactions; Patients; Pennsylvania; Perfusion; Pharmaceutical Preparations; Phenotype; Physical Function; Plasma; Plasma Proteins; Play; Procedures; Production; Proteins; Publications; Publishing; Pulmonary Edema; Pulmonary Hypertension; Quality of life; Receptor Signaling; Reperfusion Injury; Research; Research Infrastructure; Research Personnel; Research Training; Respiratory physiology; Risk; Risk Factors; Role; Services; Signal Pathway; Solid; Syndrome; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Transplant Recipients; Transplantation; Universities; Variant; allograft rejection; career development; cohort; complement pathway; design; experience; functional outcomes; genetic epidemiology; genetic risk factor; genetic variant; immune activation; implantation; improved; insight; macrophage; meetings; monocyte; mortality; multidisciplinary; novel; patient oriented; primary outcome; prospective; protein expression; response; skills; therapeutic development; transplantation medicine

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.

描述（申请人提供）：该提议的广泛目标是1）评估肺中全身和局部的长五聚蛋白-3（PTX 3）遗传变异对肺移植后原发性移植物功能障碍（PGD）的发展的不同影响~ 2）确定PTX 3基因表达、蛋白质产生、和补体激活对PGD发展的影响~ 3）检测PTX 3遗传变异和早期PTX 3产生对闭塞性细支气管炎（BOS）发展的影响，或慢性同种异体移植物排斥反应~和4）为申请人提供成为以患者为导向的临床研究的独立研究者所需的技能，知识和经验。PGD在肺移植后是常见的，影响高达30%的所有受体，并导致以延长住院时间和机械通气以及身体和肺功能不良、早期死亡和BOS风险增加的形式的发病率增加。PGD可能主要由同种异体移植物植入时的严重缺血再灌注损伤引起。在这种情况下，先天性免疫应答可能上调，然而，它们的机制作用以及全身性和肺特异性应答之间的重要差异仍然知之甚少。我们已经发表了两项研究，证明增加的PTX 3血浆水平和PTX 3基因中的常见变异与PGD风险增加相关。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种关系中起着不可或缺的作用。该提议利用宾夕法尼亚大学的现有基础设施来开发良好表型的群组，以研究PTX 3与PGD和BOS的关联的“基因-功能”机制。这项前瞻性队列研究将用于评价PTX 3循环单核细胞和肺巨噬细胞基因表达、PTX 3蛋白浓度和补体激活作为暴露、PTX 3基因型和肺移植后PGD结局之间因果途径的介质所发挥的作用。通过严格的培训计划，涉及先进的统计分析和遗传流行病学教学，从建立临床研究者的指导，以及深入的研究经验，申请人将获得在队列设计和开发，分子实验室技术，因果途径和纵向数据分析，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基准，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轻松的协作，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。该提案将使申请人能够为肺移植医学领域做出重大贡献，发展成为 作为一名独立的临床研究者，他为未来成功的R 01资助的项目做好准备，这些项目旨在开发针对先天免疫遗传风险因素的PGD治疗方法。