Host Response, Lung Microbiome, and Clinical Phenotype in Hypersensitivity Pneumonia

项目总结/摘要 Margaret Salisbury，MD，MS是密歇根大学的肺部和重症监护医生。这 K23指导职业发展应用程序包括协调的5年培训和研究计划 旨在推动索尔兹伯里博士朝着她成为独立的长期目标的活动 从事以患者为导向的纤维化间质性肺疾病（ILD）研究的医生兼科学家。ILD影响 高达1/14的美国成年人，其中过敏性肺炎（HP）流行。HP结果 从抗原吸入后免疫系统激活，并且在临床方面是异质性的， 介绍和疾病生物学。纤维化形式与生存率低相关， 特发性肺纤维化（IPF）。宿主免疫反应和微生物存在于 肺（“肺微生物组”）可能影响ILD结果。了解这些生物变量 与纤维化和疾病进展相关，代表了开发有效的、个性化的 HP和其他纤维化ILD患者的治疗，从而改善这些生命的预后， 威胁性疾病本项目的具体目的是：1）确定ILD诊断之间的差异 组（例如HP和IPF）在宿主免疫应答和肺微生物组组成中的作用 诊断;和2）确定关键的宿主免疫应答和预测后续免疫应答的肺部微生物组标志物。 肺功能改变。为了实现这些目标，Salisbury博士将进行一项ILD的前瞻性队列研究 接受诊断性肺部采样程序的患者，具有宿主应答和肺部微生物组标志物 在同时收集的支气管肺泡灌洗液中测量。确定的HP和IPF患者将接受 在诊断程序后的一年中进行连续肺功能测量。混合效应 模型将确定基线宿主反应和微生物组变量，这些变量独立预测肺部感染。 函数轨迹在完成这个项目后，索尔兹伯里博士将获得肺研究的经验， 免疫学、微生物生态学和临床研究方法。这些技能将补充她现有的 ILD患者临床护理专业知识，并已完成临床研究教学培训 方法.培训计划包括临床试验专家的强化指导（Kevin Flaherty，MD MS）、肺免疫学（Bethany摩尔，博士）、微生物生态学（加里·赫夫纳格尔，博士）和生物统计学 （苏珊·默里，ScD），选择课程，并参与科学界。完成本 一个逐步独立的研究项目将导致对宿主的治疗操作的研究 在随后的R 01、U 01和/或R21应用中的免疫应答和/或肺微生物组。索尔兹伯里医生 独特的资源包括获得一个专门的团队的共同导师和顾问，她有长期- 长期合作。密歇根大学拥有出色的研究基础设施，积极 支持初级调查员，并提供相关学科的高级课程。

PROJECT SUMMARY/ABSTRACT Margaret Salisbury, MD, MS is a Pulmonary and Critical Care physician at the University of Michigan. This K23 mentored career development application includes a coordinated 5-year plan of training and research activities designed to advance Dr. Salisbury toward her long-term goal of becoming an independent physician-scientist conducting patient-oriented research on fibrotic interstitial lung disease (ILD). ILD affects up to 1 in 14 American adults, with hypersensitivity pneumonia (HP) prevalent among these. HP results from immune system activation following antigen inhalation, and is heterogeneous in terms of clinical presentation and disease biology. The fibrotic form is associated with poor survival and a comparable course to idiopathic pulmonary fibrosis (IPF). The host immunologic response and microbes present in the lungs (the “lung microbiome”) likely influence ILD outcomes. Understanding how these biologic variables relate to fibrosis and disease progression represents a key step toward developing effective, personalized treatments for patients with HP and other fibrotic ILD, thereby improving the prognosis of these life- threatening diseases. The specific Aims of this project are to: 1) Identify differences across ILD diagnosis groups (e.g. HP and IPF) in the host immune response and lung microbiome composition at the time of diagnosis; and 2) Identify key host immune response and lung microbiome markers that predict subsequent lung function change. To complete these aims, Dr. Salisbury will conduct a prospective cohort study of ILD patients undergoing diagnostic lung sampling procedures, with host response and lung microbiome markers measured in concurrently-collected bronchoalveolar lavage fluid. Identified HP and IPF patients will undergo serial pulmonary function measurement in the year following the diagnostic procedure. Mixed effects models will identify baseline host response and microbiome variables independently predictive of pulmonary function trajectory. In completion of this project, Dr. Salisbury will gain experience in the study of lung immunology, microbial ecology, and clinical research methods. These skills will complement her existing expertise in clinical care of patients with ILD, and already-completed didactic training in clinical research methods. The training plan includes intensive mentorship by experts in clinical trials (Kevin Flaherty, MD MS), lung immunology (Bethany Moore, PhD), microbial ecology (Gary Huffnagle, PhD), and biostatistics (Susan Murray, ScD), select coursework, and participation in a scientific community. Completion of this progressively independent research project will lead to study of therapeutic manipulation of the host immune response and/or lung microbiome in subsequent R01, U01, and/or R21 applications. Dr. Salisbury’s unique resources include access to a dedicated team of co-mentors and advisors with whom she has long- standing collaborations. The University of Michigan has an outstanding research infrastructure, actively supports junior investigators, and offers advanced courses in relevant disciplines.