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 内科医生、科学家和间质性肺疾病(ILD)患者导向研究的领导者，重点是 过敏性肺炎(HP)的表型与治疗每14名美国成年人中就有1人患有ILD， 其中惠普占了上风。HP是由吸入抗原后的免疫系统激活引起的， 在临床表现和疾病生物学方面是不同的。纤维性形式与 存活率低，病程与特发性肺纤维化(IPF)相当。宿主免疫学 肺部的反应和微生物(“肺微生物群”)可能影响ILD的结果。 了解这些生物变量如何与纤维化和疾病进展相关是关键的一步 为幽门螺杆菌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。该项目的具体目标是：1)确定ILD之间的差异 诊断组在诊断时的宿主免疫反应和肺微生物群组成； 2)确定预测肺功能变化的关键宿主免疫反应和肺微生物组标志物 在HP和IPF人群中。为了实现这些目标，索尔兹伯里博士将进行一项前瞻性的队列研究 接受诊断性肺采样的ILD患者的宿主反应和肺微生物群 同时收集的支气管肺泡灌洗液中测量的标志物。确诊的HP和IPF患者将 在诊断程序后的第二年进行连续肺功能测定。混和 效应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研究 肺免疫学、微生物生态学、临床研究方法。这些技能将与她相辅相成 在ILDS患者的临床护理方面拥有现有的专业知识，并已完成临床教学培训 研究方法。培训计划包括临床试验专家的强化指导(凯文 Flaherty，医学硕士，主要导师)，肺免疫学(Bethany Moore，博士)，微生物生态学(Gary Huffnagle，PhD)和生物统计学(Susan Murray，ScD)，精选课程，并参与科学 社区。这个逐步独立的研究项目的完成将导致对治疗的研究 在随后的R01、U01和/或R21中对宿主免疫反应和/或肺微生物组的操纵 申请。索尔兹伯里博士的独特资源包括接触到一个专门的指导团队， 她有长期的合作关系。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 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.