Role of MMP10 in Macrophage Activation

MMP10 在巨噬细胞激活中的作用

• 批准号: 9130372
• 负责人: WILLIAM C PARKS
• 金额: $ 53.99万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-08 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130372
• 关键词: Acute; Affect; Allergens; Bleomycin; Cell Surface Proteins; Cells; Chronic; Cicatrix; Collagen; Data; Endopeptidases; Environment; Epithelium; Extracellular Matrix; Family; Fibrillar Collagen; Fibrosis; Gene Expression; Health; Homing; Human; Immune; Immune response; Immunosuppressive Agents; Infection; Inflammation; Inflammatory; Injury; Knowledge; Leukocytes; Lung; Lung diseases; Macrophage Activation; Matrix Metalloproteinases; Mediating; Membrane Proteins; Metalloproteases; Modeling; Mus; Peptide Hydrolases; Phenotype; Pneumonia; Process; Production; Proteins; Pseudomonas aeruginosa; Pulmonary Emphysema; Role; Shapes; Signal Transduction; Skin; Stimulus; System; Testing; Tissues; Work; alveolar destruction; base; collagenase; environmental tobacco smoke exposure; extracellular; injured; interstitial; lung injury; macrophage; member; mouse model; novel; programs; repaired; response; stromelysin 2

 DESCRIPTION (provided by applicant): This new project will explore how distinct subsets of macrophages remodel excess airway extracellular matrix (ECM) that builds up in response to lung injury, infection, or allergen challenge. 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 ECM-degrading programs in alternatively activated 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 drives 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 hypothesis that MMP10 is induced in response to specific stimuli in an injured/infected tissue environment and sheds a cell-surface protein on macrophage and that loss of this protein initiates signaling to turn on ECM-remodeling programs in M2-biased macrophages. The aims are to 1) determine the mechanisms controlling MMP10 expression in macrophages and role of MMP10 in models of lung disease; 2) identity the ECM-degrading proteinases expressed by M2 macrophages; 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 various analytical approaches.

 描述（由申请人提供）：这个新项目将探索不同的巨噬细胞亚群如何重塑因肺损伤、感染或过敏原挑战而形成的过量气道细胞外基质（ECM）。机制重点将集中于基质溶素-2 (MMP10)（细胞外内肽酶基质金属蛋白酶家族的成员）如何以细胞自主方式发挥作用，以控制替代激活的巨噬细胞中 ECM 降解程序的激活。关键的初步数据表明，MMP10 在巨噬细胞中被诱导，并驱动其激活状态从促炎细胞（即 M1 偏向）转变为免疫抑制性巨噬细胞（即 M2 偏向）。 M2 巨噬细胞被认为具有重塑能力，另外的初步数据表明，MMP10 通过调节其他具有基质降解活性的金属蛋白酶的表达，驱动 M2 巨噬细胞中有效重塑表型的激活。该项目将测试这样的假设：MMP10 是在受伤/感染的组织环境中响应特定刺激而被诱导的，并在巨噬细胞上脱落细胞表面蛋白，而这种蛋白的丢失会启动信号传导，在偏向 M2 的巨噬细胞中开启 ECM 重塑程序。目的是1)确定控制巨噬细胞中MMP10表达的机制以及MMP10在肺部疾病模型中的作用； 2) 鉴定M2巨噬细胞表达的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各种分析方法。