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.

项目摘要/摘要 该项目描述了一项为期5年的职业发展计划，目的是培训校长 研究人员成为独立的身体科学家，他研究肺部宿主 - 微生物相互作用 疾病。申请人是部门肺部和重症监护部的临床讲师 宾夕法尼亚大学Perelman医学院的医学。他是由罗纳德（Ronald）指导的 医学博士科尔曼（Collman）是医学和微生物学教授，也是肺微生物组领域的先驱 也是分子病毒学专家。 MSCE医学博士Jason Christie是医学和流行病学教授 他是一名分子流行病学家，在肺移植并发症方面具有专业知识和使用 生物统计学方法来模拟复杂的肺部疾病。研究计划使用临床翻译方法 和计算生物学，以获得对肺中宿主 - 微生物组相互作用后的机械理解 移植及其在慢性肺同种异移植功能障碍（CLAD）中的作用 - 移植物的最常见原因 移植后一年后的失败和死亡。该建议直接回应了NHLBI的战略愿景 目的了解微生物组对肺部健康的影响。 在该K23奖的支持下，McGinniss博士将在AIM 1中分析支气管肺泡的微生物组 来自肺部移植患者的纵向队列研究的灌洗液（BAL）。他会使用 先进的生物统计学方法，以了解早期肺微生物组营养不良的关系 - 改变 在移植后的第一年和随后的甲板后的第一年，组成，相对抽象或功能。 在AIM 2中，他将对24例病例和24个匹配的对照组进行外壳案例对照研究。他将参加决赛 12例和12个对照。他将使用这项病例对照研究进行微生物组的多词分析 和宿主的反应，以了解外壳的机制。在AIM 3中，他将使用公正的代谢组学来 发现新颖的生物标志物并询问外壳中的代谢失调。他还将评估角色 代谢组具有介导病理宿主 - 微生物相互作用。此外，他将对 纵向队列研究中的代谢组和炎症标志物评估它们是否在 诊断外壳。 McGinniss博士概述了课程工作，技能获取的严格培训计划（重点是临床 - 翻译方法，计算生物学和先进的宏基因组学）和职业发展。他有 组建了一个区别，多学科的心态团队，以实现这一愿景。宾夕法尼亚州提供了特殊的 这项提案的智力和协作环境，并在Pennchop中进行考虑 微生物组计划和转化医学治疗研究所（ITMAT）将被利用 这个奖项。 McGinniss博士的位置良好，可以成功地竞争目标和培训计划，以便他将 成为R01奖的竞争申请人，进一步探讨慢性肺部疾病中宿主菌相互作用。