Control of Macrophage Activation in Lung Disease

肺部疾病中巨噬细胞激活的控制

基本信息

批准号：
9898443
负责人：
WILLIAM C PARKS
金额：
$ 60.35万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9898443
关键词：
Acute Affect Anti-Inflammatory Agents Area Bleomycin Cell Surface Proteins Cells Chronic Cicatrix Collagen Data Endopeptidases Epithelial Epithelium Extracellular Matrix Family Fibrosis Homing Human Immune Immune response Infection Inflammation Inflammatory Injury Knowledge Leukocytes Lung Lung diseases Macrophage Activation Matrix Metalloproteinases Metalloproteases Modeling Mus Peptide Hydrolases Phenotype Process Production Proteins Pseudomonas aeruginosa pneumonia Publishing Pulmonary Emphysema Pulmonary Fibrosis Role Signal Transduction Site Skin System Testing Tissues Work acute infection alveolar destruction collagenase epithelial injury exposure to cigarette smoke extracellular immunoregulation immunosuppressive macrophages interstitial lung injury macrophage member mouse model novel programs repaired response stromelysin 2

项目摘要

ABSTRACT This project will explore how distinct subsets of macrophages moderates inflammation and remodel excess airway extracellular matrix (ECM) that builds up in response to lung injury. The mechanistic focus will center on how stromelysin-2 (MMP10), a member of the matrix metalloproteinase family of extracellular endopeptidases, functions in a cell-autonomous manner to control the activation of immunosuppressive and ECM-degrading programs in macrophages. Key preliminary data demonstrate that MMP10 is induced in macrophages and functions to drive their activation status from pro-inflammatory cells (i.e., M1-biased) to immunosuppressive macrophages (i.e., M2-biased). M2 macrophages are considered to be remodeling competent, and additional preliminary data demonstrates that MMP10 promotes the activation of an effective remodeling phenotype in M2 macrophages by regulating the expression of other metalloproteinases with matrix-degrading activity. This project will test the hypotheses that MMP10 sheds a cell-surface protein on macrophage and that loss of this protein initiates signaling to turn on immuno-regulatory and ECM-remodeling programs in M2-biased macrophages. The aims are to 1) determine the role of MMP10 in regulating macrophage activation and immunosuppressive function in lung fibrosis.; 2) identity the ECM-degrading proteinases controlled by MMP10; and 3) identify and validate the MMP10 substrate affecting macrophage activation. The approach will include the use of genetically-defined mouse models, mouse and human cells, and analytical approaches.

抽象的该项目将探索巨噬细胞的不同亚群如何调节炎症和重塑过度气道细胞外基质 (ECM) 是因肺损伤而形成的。机械重点将集中在胞外肽链内切酶基质金属蛋白酶家族成员 stromelysin-2 (MMP10) 是如何以细胞自主方式发挥作用，控制免疫抑制和 ECM 降解的激活巨噬细胞中的程序。关键的初步数据表明，MMP10 在巨噬细胞中被诱导，并且驱动其激活状态从促炎细胞（即 M1 偏向）转变为免疫抑制细胞巨噬细胞（即 M2 偏向）。 M2 巨噬细胞被认为具有重塑能力，并且额外初步数据表明，MMP10 促进有效重塑表型的激活 M2 巨噬细胞通过调节其他具有基质降解活性的金属蛋白酶的表达。这该项目将测试以下假设：MMP10 在巨噬细胞上脱落细胞表面蛋白，以及这种蛋白的丢失蛋白质启动信号传导以开启 M2 偏向性的免疫调节和 ECM 重塑程序巨噬细胞。目的是 1) 确定 MMP10 在调节巨噬细胞激活中的作用和肺纤维化中的免疫抑制功能。 2) 鉴定由MMP10控制的ECM降解蛋白酶； 3) 鉴定并验证影响巨噬细胞活化的 MMP10 底物。该方法将包括使用基因定义的小鼠模型、小鼠和人类细胞以及分析方法。