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

项目摘要/摘要 玛格丽特·索尔兹伯里，医学博士，医学硕士，密歇根大学肺部和重症监护内科医生。这 K23辅导式职业发展申请包括一个协调的5年培训和研究计划 旨在推动索尔兹伯里博士朝着成为独立医生的长期目标前进的活动 从事以病人为中心的纤维性间质性肺病(ILD)研究的内科科学家。ILD影响 每14名美国成年人中就有1人患有过敏性肺炎(HP)。惠普结果 来自抗原吸入后的免疫系统激活，在临床上是不同的 陈述与疾病生物学。纤维化形式与较差的存活率和可比的 病程进展为特发性肺纤维化(IPF)。宿主免疫反应和体内存在的微生物 肺部(“肺部微生物群”)可能会影响ILD的预后。了解这些生物变量是如何 与纤维化和疾病进展相关是发展有效、个性化的关键一步 治疗幽门螺杆菌和其他纤维性ILD患者，从而改善这些人的预后- 威胁人类的疾病。该项目的具体目标是：1)确定ILD诊断的差异 宿主免疫反应和肺微生物群组成时的群组(如Hp和IPF) 诊断；以及2)确定关键的宿主免疫反应和肺微生物组标志物，预测随后的 肺功能改变。为了实现这些目标，索尔兹伯里博士将对ILD进行前瞻性队列研究 接受诊断性肺采样程序的患者，宿主反应和肺微生物组标志物 在同时收集的支气管肺泡灌洗液中测量。确诊的HP和IPF患者将接受 在诊断程序后的一年内进行连续肺功能测量。混合效果 模型将确定基线宿主反应和微生物组变量独立预测肺 功能轨迹。在完成这个项目后，索尔兹伯里博士将获得肺病研究的经验。 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患者的临床护理专业知识，以及已完成的临床研究教学培训 方法：研究方法。培训计划包括临床试验专家的强化指导(Kevin Flaherty，医学博士 医学硕士)、肺部免疫学(贝瑟妮·摩尔博士)、微生物生态学(Gary Huffnagle博士)和生物统计学 (苏珊·默里，SCD)，选择课程作业，并参与科学社区。完成这项工作 逐步独立的研究项目将导致对宿主治疗手法的研究 在随后的R01、U01和/或R21应用中的免疫反应和/或肺微生物组。索尔兹伯里医生的 独特的资源包括与她长期合作的合作导师和顾问组成的专门团队- 长期合作。密歇根大学拥有出色的研究基础设施， 支持初级调查人员，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.