Interstitial macrophages in cigarette smoke-induced small airway remodeling

项目摘要 项目概要：该提案描述了一个为期5年的研究培训计划，将培养帕特里克博士 休谟成为一个独立的基础和翻译的医生科学家调查。他的长期职业目标是 通过阐明靶点来阻断或修复慢性阻塞性肺病和巨噬细胞生物学领域， 吸烟者小气道疾病的发展。在K 08奖期间，休姆博士将获得具体的 职业发展培训和导师制与创新研究计划紧密结合。他拟 研究Lyve-1阳性间质巨噬细胞在小气道病变中的作用 慢性吸烟的危害鉴于对COPD的广泛适用性，这项工作与NHLBI直接相关。 候选人：帕特里克人类医学博士，博士是一个委员会认证的肺和重症监护医学医生- 科学家在国家犹太人健康在丹佛，公司。培训和 科学出版物表明了坚定的承诺，作为一个学术临床科学家的职业生涯。 培训：拟议的职业发展计划增强了Hume博士在其职业生涯中的前期指导研究。 本科生、博士生、住院医师和研究员培训。他建议满足他的短期 通过国际知名专家的密集指导， 巨噬细胞生物学和COPD发病机制，在（i）数据分析，（ii） 细胞生物学，（iii）透明质酸信号传导，（iv）科学写作和演示，以及（v）实验室领导。 导师/环境：Hume博士与经验丰富的导师有着密切的工作关系， 在巨噬细胞和肺生物学方面贡献专业知识的合作者（Janssen和Petrache博士），COPD 发病机制和透明质酸信号传导（Petrache博士），基质金属蛋白酶生物学和组织 重塑（Redente博士），创建转基因小鼠模型（Matsuda博士）和基于设计的体视学 (Dr.史密斯）。拟议的活动将设在国家犹太人健康，一个顶级的研究机构。 研究项目：该提案的主要目的是确定支气管周围 间质性巨噬细胞（PBIM）介导气道壁重塑和慢性炎症反应的发病机制 香烟烟雾暴露。具体来说，我们的研究将检验Lyve-1在一个子集上表达的假设， 的PBIM与透明质酸结合，导致基质金属蛋白酶9（MMP-9）的产生，导致气道炎症。 壁重塑和纤维化。这将在人和鼠肺组织中进行测试，使用定量 形态测定和免疫荧光，流式细胞术，透明质酸信号传导的体外模型， 转基因动物模型在这样做时，Lyve-1+ PBIM募集、MMP-9和MMP-10之间的特定关系可以被解释为： 产生和气道壁重塑将被阐明。

PROJECT SUMMARY Project Summary: This proposal describes a 5-year research training program that will develop Dr. Patrick Hume into an independent basic and translational physician-scientist investigator. His long-term career goal is to advance the fields of COPD and macrophage biology through the elucidation targets to block or repair the development of small-airways disease in cigarette smokers. During this K08 Award, Dr. Hume will gain specific career development training and mentorship closely aligned with an innovative research plan. He proposes to study the role of Lyve-1 positive interstitial macrophages in the development of small airway pathology induced by chronic cigarette smoke. Given the broad applicability to COPD, this work is directly relevant to the NHLBI. Candidate: Patrick Human MD, PhD is a board-certified Pulmonary and Critical Care Medicine physician- scientist at National Jewish Health in Denver, CO. His record of basic science research, Ph.D. training and scientific publications demonstrates a firm commitment to a career as an academic clinician-scientist. Training: The proposed career development plan augments Dr. Hume’s prior mentored research during his undergraduate, doctoral, medical residency and fellowship training. He proposes to meet his short-term objectives through an integrated combination of intensive mentoring by internationally renowned experts in macrophage biology and COPD pathogenesis with didactic and hands-on experiences in (i) data analysis, (ii) cell biology, (iii) hyaluronic acid signaling, (iv) scientific writing and presentation, and (v) laboratory leadership. Mentor / Environment: Dr. Hume has close working relationships with highly experienced mentors and collaborators who contribute expertise in macrophage and lung biology (Drs. Janssen and Petrache), COPD pathogenesis and hyaluronic acid signaling (Dr. Petrache), matrix metalloproteinase biology and tissue remodeling (Dr. Redente), creation of transgenic mouse models (Dr. Matsuda) and design-based stereology (Dr. Smith). The proposed activities will be based at National Jewish Health, a top-ranked research institution. Research Project: The primary objective of this proposal is to identify the mechanism by which peribronchial interstitial macrophages (PBIMs) mediate airway wall remodeling and pathogenesis in response to chronic cigarette smoke exposure. Specifically, our studies will test the hypothesis that Lyve-1 expressed on a subset of PBIMs binds to hyaluronic acid resulting in matrix metalloproteinase 9 (MMP-9) production, leading to airway wall remodeling and fibrosis. This will be tested in human and murine lung tissue using quantitative morphometry and immunofluorescence, flow cytometry, in vitro models of hyaluronic acid signaling, and transgenic animal models. In doing so, the specific relationships between Lyve-1+ PBIM recruitment, MMP-9 production, and airway wall remodeling will be elucidated.