Interstitial macrophages in cigarette smoke-induced small airway remodeling

间质巨噬细胞在香烟烟雾诱导的小气道重塑中的作用

基本信息

批准号：
10370226
负责人：
Patrick Scott Hume
金额：
$ 15.83万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10370226
关键词：
Address Airway Disease Alveolar Macrophages Animal Model Aorta Award Basic Science Binding Biology Blood Circulation CD44 gene Cause of Death Cells Cellular biology Chronic Chronic Obstructive Pulmonary Disease Cicatrix Cigarette Cigarette Smoker Collagen Critical Care Data Data Analyses Deposition Development Development Plans Doctor of Philosophy Dropout Embryo Endothelium Environment Extracellular Matrix Fellowship Fibroblasts Fibrosis Flow Cytometry Gelatin Gelatinase B Goals Health Human Hyaluronic Acid Hyaluronic Acid Binding Immunofluorescence Immunologic In Situ Individual Infiltration Inflammation Inflammatory Injury Institution International Laboratories Lead Leadership Ligation Link Location Lung Lymphatic function MMP9 gene Matrix Metalloproteinases Mediating Medical Residency Medicine Mentors Mentorship Metalloproteases Metalloproteins Molecular Weight Mus Myofibroblast National Heart, Lung, and Blood Institute Pathogenesis Pathologic Pathology Physicians Play Population Production Public Health Publications Research Research Personnel Research Project Grants Research Training Role Scientist Signal Transduction Smoke Smoker Structure of parenchyma of lung Surface Terminal Bronchiole Testing Tissues Training Training Programs Transgenic Animals Transgenic Mice Work Writing airway obstruction airway remodeling asthma model base career career development cigarette smoke cigarette smoke-induced cigarette smoking design experience exposure to cigarette smoke follower of religion Jewish in vitro Model innovation interstitial lymphatic vessel macrophage monocyte morphometry mouse model novel therapeutics receptor recruit repaired response small airways disease smoking-related lung disease therapeutic target transcriptome sequencing translational physician undergraduate student uptake

项目摘要

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.

项目概要项目摘要：该提案描述了一个为期 5 年的研究培训计划，该计划将培养帕特里克博士休谟成为一名独立的基础和转化医学科学家研究者，他的长期职业目标是。通过阐明阻断或修复慢性阻塞性肺病和巨噬细胞生物学的目标来推进慢性阻塞性肺病和巨噬细胞生物学领域的发展吸烟者小气道疾病的发展在这次 K08 奖中，休姆博士将获得具体的成果。他建议将职业发展培训和指导与创新研究计划紧密结合。研究 Lyve-1 阳性间质巨噬细胞在小气道病理发展中的作用鉴于慢性阻塞性肺病的广泛适用性，这项工作与 NHLBI 直接相关。候选人：Patrick Human MD、PhD 是一位经过委员会认证的肺科和重症监护医学医师 - 科罗拉多州丹佛国家犹太健康中心的科学家。他的基础科学研究、博士学位培训记录和科学出版物表明了对学术临床医生科学家职业生涯的坚定承诺。培训：拟议的职业发展计划增强了休谟博士之前在他的指导下的研究他建议接受本科、博士、住院医师和进修培训。通过国际知名专家的集中指导的综合组合来实现目标巨噬细胞生物学和慢性阻塞性肺病发病机制，以及 (i) 数据分析、(ii) 方面的教学和实践经验细胞生物学，(iii) 透明质酸信号转导，(iv) 科学写作和演示，以及 (v) 实验室领导。导师/环境：休谟博士与经验丰富的导师和贡献巨噬细胞和肺生物学专业知识的合作者（Janssen 和 Petrache 博士）、慢性阻塞性肺病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）、转基因小鼠模型的创建（Matsuda 博士）和基于设计的体视学（史密斯博士）。拟议的活动将在顶级研究机构国家犹太健康中心进行。研究项目：该提案的主要目标是确定支气管周围间质巨噬细胞（PBIM）介导气道壁重塑和发病机制以应对慢性病具体来说，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) 产生，从而导致气道这将在人类和小鼠肺组织中进行定量测试。形态测量和免疫荧光、流式细胞术、透明质酸信号传导的体外模型，以及在此过程中，研究了 Lyve-1+ PBIM 募集、MMP-9 之间的具体关系。将阐明生产和气道壁重塑。