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: 8898906
• 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/8898906
• 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; Therapy trial; 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; targeted treatment; 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（由申请人提供）：该提案的主要目标是 1) 评估肺部系统和局部长正五聚蛋白 3 (PTX3) 遗传变异对肺移植后原发性移植物功能障碍 (PGD) 发展的差异影响 ~ 2) 使用因果介质分析确定 PTX3 基因表达、蛋白质产生和补体激活对 PGD 发展的影响 ~ 3) 检查 PTX3 遗传变异和早期 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) 为申请人提供成为以患者为导向的临床研究中的独立研究者所需的技能、知识和经验。 PGD​​ 在肺移植后很常见，影响高达 30% 的受者，并导致发病率增加，表现为住院时间延长和机械通气时间延长、身体和肺功能差、过早死亡以及 BOS 风险增加。 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，先天免疫反应可能会上调〜然而，它们的机制作用以及全身和肺部特异性反应之间的重要差异仍然知之甚少。我们发表了两项研究，证明 PTX3 血浆水平升高和 PTX3 基因常见变异与 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，基因表达的增加和补体激活在这种关系中发挥着不可或缺的作用。该提案利用宾夕法尼亚大学的现有基础设施开发一个表型良好的队列来研究 PTX3 与 PGD 和 BOS 关联的“基因到功能”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暴露、PTX3 基因型和肺移植后结果、PGD 之间因果途径中介质的作用。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、成熟临床研究人员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、因果路径和纵向数据分析以及肺移植结果流行病学方面的技能。为了确保申请人达到研究、出版和职业发展的所有基准，他将定期与他的主要导师和多学科导师团队举行会议。除了导师之外，候选人的环境还将提供轻松的协作、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在肺移植医学领域做出重大贡献，发展成为 一名独立的临床研究者，并为他未来成功的 R01 资助项目做好准备，该项目旨在开发针对先天免疫遗传风险因素的 PGD 疗法。