Control of Macrophage Activation in Lung Disease

肺部疾病中巨噬细胞激活的控制

• 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
• 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

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.

摘要