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 医生-科学家，间质性肺病（ILD）患者导向研究的领导者，重点是 过敏性肺炎（HP）的表型和治疗。ILD影响高达1/14的美国成年人， 其中，HP占主导地位。HP由抗原吸入后免疫系统激活引起， 在临床表现和疾病生物学方面是异质性的。纤维化形式与 生存率低，病程与特发性肺纤维化（IPF）相似。宿主免疫学 肺中存在的微生物（“肺微生物组”）可能影响ILD的结果。 了解这些生物学变量与纤维化和疾病进展的关系是关键的一步 为HP患者开发有效的个性化治疗，从而改善预后 这种威胁生命的疾病。本项目的具体目的是：1）确定ILD之间的差异 诊断组在诊断时的宿主免疫应答和肺部微生物组组成; 和2）鉴定预测肺功能变化的关键宿主免疫应答和肺微生物组标志物 HP和IPF人群。为了完成这些目标，索尔兹伯里博士将进行一项前瞻性队列研究， 接受诊断性肺采样程序的ILD患者，有宿主应答和肺微生物组 在同时收集的支气管肺泡灌洗液中测量的标志物。确定的HP和IPF患者将 在诊断程序后的一年内进行连续的肺功能测量。混合 效应模型将确定基线宿主反应和微生物组变量， 肺功能轨迹在这个项目完成后，索尔兹伯里博士将获得经验的研究， 肺免疫学、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，以及已经完成的临床教学培训 研究方法培训计划包括临床试验专家的强化指导（Kevin Flaherty，MD MS，主要导师），肺免疫学（Bethany摩尔，博士），微生物生态学（加里 Huffnagle，博士）和生物统计学（Susan Murray，ScD），选择课程，并参与科学 社区这个逐步独立的研究项目的完成将导致治疗研究 在随后的R 01、U 01和/或R21中操纵宿主免疫应答和/或肺微生物组 应用.索尔兹伯里博士的独特资源包括获得一个专门的导师团队， 她有长期的合作。密歇根大学有一项杰出的研究 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 and leader in interstitial lung disease (ILD) patient-oriented research, with a focus on phenotyping and treatment of hypersensitivity pneumonia (HP). ILD affects up to 1 in 14 American adults, with 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, thereby improving the prognosis of this life-threatening disease. The specific Aims of this project are to: 1) Identify differences across ILD diagnosis groups 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 lung function change in HP and IPF populations. 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 ILDs, and already-completed didactic training in clinical research methods. The training plan includes intensive mentorship by experts in clinical trials (Kevin Flaherty, MD MS, primary mentor), 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 mentorship team 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.