Host-microbiome interactions after lung transplantation and chronic lung allograft dysfunction

肺移植后宿主-微生物组相互作用和慢性同种异体肺移植功能障碍

• 批准号: 10190611
• 负责人: John Evan McGinniss
• 金额: $ 19.39万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10190611
• 关键词: Accounting; Activities of Daily Living; Address; Allografting; Anaerobic Bacteria; Award; Azithromycin; Bacterial Genes; Biological; Biological Assay; Biometry; Biostatistical Methods; Bronchoalveolar Lavage Fluid; Case-Control Studies; Cessation of life; Chronic; Chronic lung disease; Clinical; Cohort Studies; Collection; Complex; Computational Biology; Conflict (Psychology); Critical Care; Data Analyses; Development; Development Plans; Diagnosis; Disease; Enrollment; Epidemiologist; Epidemiology; Functional disorder; Funding; Goals; Health; Immune; Immune response; Incidence; Infection; Inflammation; Inflammatory; Institutes; Knowledge; Link; Longitudinal cohort study; Lung; Lung Transplantation; Lung diseases; Measures; Mediating; Mediator of activation protein; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metabolic; Metagenomics; Methodology; Methods; Microbe; Microbial Genetics; Microbiology; Modeling; Molecular; Molecular Virology; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Organ Transplantation; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patient Care; Patients; Pennsylvania; Phenotype; Physicians; Play; Positioning Attribute; Principal Investigator; Prognostic Marker; Prospective cohort study; Research; Research Personnel; Resources; Ribosomal RNA; Risk; Role; Sampling; Scientist; Shotguns; Site; Solid; Taxonomy; Techniques; Testing; Therapeutic; Time; Training; Translational Research; Transplant Recipients; Transplantation; Transplanted Lung Complication; Universities; Vision; Work; advanced analytics; career development; case control; collaborative environment; cytokine; density; diagnostic biomarker; dysbiosis; effective therapy; graft failure; host microbiome; host-microbe interactions; improved; individual variation; inflammatory marker; insight; instructor; longitudinal analysis; loss of function; lung allograft; lung microbiome; medical schools; metabolome; metabolomics; metagenomic sequencing; microbial; microbial composition; microbiome; microbiome analysis; microorganism interaction; mortality; multidisciplinary; multiple omics; novel; novel marker; oral anaerobes; pathogen; post-transplant; professor; programs; pulmonary function; recruit; response; sample collection; skill acquisition; translational medicine

PROJECT SUMMARY/ABSTRACT This project describes a 5-year mentored career development plan with the goal of training the principal investigator to become an independent physician-scientist who investigates host-microbe interactions in lung disease. The applicant is a Clinical Instructor in the Pulmonary and Critical Care Division of the Department of Medicine at the Perelman School of Medicine at the University of Pennsylvania. He is mentored by Ronald Collman, MD who is a Professor of Medicine and Microbiology and a pioneer in the lung microbiome field and also an expert in molecular virology. Jason Christie, MD, MSCE is a Professor of Medicine and Epidemiology who is a molecular epidemiologist with expertise in complications of lung transplantation and the use of biostatistical methods to model complex lung disease. The research plan uses clinical-translational methodology and computational biology to gain mechanistic understanding of host-microbiome interactions in the lung after transplantation and their role in chronic lung allograft dysfunction (CLAD)—the most common cause of graft failure and death after one-year post-transplant. This proposal responds directly to NHLBI’s Strategic Vision objective to understand the influence of the microbiome on lung health. With the support of this K23 award, Dr. McGinniss will in Aim 1 analyze the microbiome of bronchoalveolar lavage fluid (BAL) from a longitudinal cohort study of lung transplant patients at risk of CLAD. He will use advanced biostatistical approaches to understand the relation of early lung microbiome dysbiosis—changes in the composition, relative abundance, or function of microbes—in the first year after transplant and later CLAD. In Aim 2 he will create a CLAD case-control study of 24 cases and 24 matched controls. He will enroll the final 12 cases and 12 controls. He will use this case-control study to perform a multi-omic analysis of the microbiome and host responses to understand mechanisms of CLAD. In Aim 3, he will use unbiased metabolomics to discover novel biomarkers and to interrogate metabolic dysregulation in CLAD. He will also assess the role the metabolome has in mediating pathological host-microbe interactions. In addition, he will do targeted analysis of the metabolome and inflammatory markers in longitudinal cohort study to assess if they are aberrant before the diagnosis of CLAD. Dr. McGinniss has outlined a rigorous training plan of coursework, skills acquisition (with a focus on clinical- translational methods, computational biology, and advanced metagenomics), and career development. He has assembled a distinguished, multidisciplinary mentorship team to realize this vision. Penn provides an exceptional intellectual and collaborative environment for this proposal with considerable resources in the PennCHOP Microbiome Program and the Institute of Translational Medicine Therapeutics (ITMAT) that will be leveraged in this award. Dr. McGinniss is well-positioned to successfully compete the aims and training plan so that he will be a competitive applicant for an R01 award further exploring host-microbe interactions in chronic lung disease.

项目概要/摘要 该项目描述了一个为期 5 年的指导式职业发展计划，旨在培训校长 调查员成为一名独立的医师科学家，研究肺部宿主与微生物的相互作用 申请人是肺科和重症监护科的临床讲师。 宾夕法尼亚大学佩雷​​尔曼医学院医学博士，由罗纳德指导。 Collman 医学博士是医学和微生物学教授，也是肺微生物组领域的先驱 Jason Christie 博士也是分子病毒学专家，医学硕士和流行病学教授。 他是一位分子流行病学家，在肺移植并发症和使用 该研究计划使用临床转化方法来模拟复杂的肺部疾病。 和计算生物学，以获得对肺部宿主-微生物组相互作用的机械理解 移植及其在慢性同种异体肺移植功能障碍（CLAD）中的作用——移植物最常见的原因 移植后一年后失败和死亡 该提案直接响应 NHLBI 的战略愿景。 目的是了解微生物组对肺部健康的影响。 在 K23 奖项的支持下，McGinniss 博士将在目标 1 中分析支气管肺泡的微生物组 他将使用来自对有 CLAD 风险的肺移植患者的纵向队列研究的灌洗液 (BAL)。 先进的生物统计学方法来了解早期肺微生物群失调的关系——肺微生物组的变化 微生物的组成、相对丰度或功能——移植后第一年和后来的 CLAD。 在目标 2 中，他将创建 24 个病例和 24 个匹配对照的 CLAD 病例对照研究。他将招募最终的患者。 他将利用这项病例对照研究对 12 个病例和 12 个对照进行微生物组的多组学分析。 和宿主反应以了解 CLAD 的机制。在目标 3 中，他将使用无偏见的代谢组学来了解 CLAD 的机制。 发现新的生物标志物并探究 CLAD 中的代谢失调，他还将评估 CLAD 中的作用。 此外，他还将对代谢组学进行有针对性的分析。 纵向队列研究中的代谢组和炎症标志物，以评估它们在治疗前是否异常 CLAD 的诊断。 McGinniss 博士概述了严格的课程作业、技能获取培训计划（重点是临床- 他拥有转化方法、计算生物学和先进的宏基因组学）和职业发展。 宾夕法尼亚大学提供了一个特殊的 PennCHOP 拥有大量资源，为该提案提供了智力和协作环境 微生物组计划和转化医学治疗研究所 (ITMAT) 将在 麦金尼斯博士有能力成功完成该奖项的目标和培训计划，使他能够 成为 R01 奖的竞争性申请人，进一步探索慢性肺病中宿主与微生物的相互作用。