The regulation of inflammation and phagocytosis by CD93

CD93对炎症和吞噬作用的调节

• 批准号: 7912512
• 负责人: Suzanne Slater Bohlson
• 金额: $ 38.5万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912512
• 关键词: Actins; Adaptor Signaling Protein; Adhesions; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Arthritis; Binding; Biological Assay; Blood Platelets; C-Type Lectins; Cause of Death; Cell Adhesion Molecules; Cell surface; Cells; Complement Activation; Cytoplasmic Tail; Cytoskeleton; Data; Defect; Development; Disease; ERM protein; Elements; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Event; Excision; Exhibits; Family; Family member; Generations; Glycoproteins; Goals; Gram-Negative Bacteria; Heart Diseases; Homeostasis; Homologous Gene; Human; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Ingestion; Injury; Lead; Lectin; Leukocytes; Lipids; Liquid substance; Macrophage Activation; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Membrane; Modeling; Molecular; Mus; Myeloid Cells; Normal tissue morphology; Pathology; Pathway interactions; Phagocytes; Phagocytosis; Phase; Phenotype; Process; Property; Proteins; Regulation; Reperfusion Injury; Reporter; Resolution; Role; Sepsis; Serum; Signal Transduction; Small Interfering RNA; Surface Plasmon Resonance; Tail; Testing; Therapeutic; Thrombomodulin; United States; Western Blotting; abstracting; cell type; cytokine; design; ezrin; in vivo; knock-down; migration; moesin; monocyte; neutrophil; new therapeutic target; novel; prevent; response to injury; small hairpin RNA; therapeutic target

Abstract While inflammation is a normal, protective response to injury, it is becoming increasingly clear that uncontrolled inflammation is integral to most disease processes including cancer and heart disease, the leading causes of death in the United States. The resolution phase of inflammation is an active process involving downmodulation of proinflammatory mediators and clearance of dead or dying cells. Understanding the molecular mechanisms involved in the resolution of inflammation will provide a framework from which to design directed therapeutics to prevent or diminish aberrant inflammation. Rapid and efficient removal of apoptotic cells is critical to the resolution of inflammation. CD93 is a cell surface molecule required for ingestion of apoptotic cells in vivo and is expressed by myeloid cells, platelets and endothelial cells: those cell types principally involved in regulation of inflammation. It belongs to the Group XIV family of transmembrane C-type lectin-like domain (CTLD) containing glycoproteins with shared functions in adhesion, migration and inflammation. We have recently identified a soluble form of CD93 that is elevated in inflammatory fluids. This proposal tests the hypothesis that CD93 regulates monocyte/macrophage activation extracellularly via its membrane tethered or soluble ectodomain, as well as intracellularly via protein and lipid interaction with the intracellular tail. Specifically, the role of CD93 in regulating inflammation in vivo will be assessed in a sepsis model using both CD93-/- mice and mice double deficient in CD93 and TM-D1, a CD93 homologue that downregulates inflammation in sepsis. Soluble CD93 will be tested for its ability to enhance ingestion of apoptotic cells and gram negative bacteria by primary human and mouse phagocytes. Anti-inflammatory properties of sCD93 will be investigated and compared to TM-D1. Membrane tethered CD93 regulates phagocytosis and adhesion in vitro, critical processes in the regulation of inflammation. Previous studies that have identified specific CD93 cytoplasmic tail interacting molecules known to be involved in cytoskeletal dynamics, such as those required for phagocytosis and adhesion, will be extended. Localization and function of these molecules during the phagocytic process will be assessed. These studies will contribute to our understanding of inflammation, and may lead to CD93 directed therapeutics to regulate this process.

抽象的 虽然炎症是对伤害的正常，保护性的反应，但它正在变成 越来越清楚的是，不受控制的炎症是大多数疾病过程不可或缺的 包括癌症和心脏病，是美国的主要死亡原因。 炎症的分辨率阶段是一个主动过程，涉及 促炎性介体和死亡或垂死细胞的清除。了解 涉及炎症分辨率的分子机制将提供 从哪些框架设计定向治疗，以防止或减少异常 炎。凋亡细胞的快速有效去除对解决至关重要 炎。 CD93是摄入凋亡细胞所需的细胞表面分子 体内，由髓样细胞，血小板和内皮细胞表达：这些细胞类型 主要参与调节炎症。它属于XIV组的家族 跨膜C型凝集素样结构域（CTLD），含有共有的糖蛋白 粘附，迁移和炎症的功能。我们最近确定了一个可溶的 CD93的形式在炎性液中升高。该提案检验了假设 该CD93通过其膜细胞外调节单核细胞/巨噬细胞激活 束缚或可溶性外域，以及细胞内通过蛋白质和脂质相互作用 带有细胞内尾巴。具体而言，CD93在调节体内炎症中的作用 将使用CD93 - / - 小鼠和小鼠双重缺陷在败血症模型中评估 CD93和TM-D1，一种CD93同源物，下调败血症的炎症。 可溶性CD93的能力将被测试，以增强凋亡细胞摄入和 原代人和小鼠吞噬细胞的革兰氏阴性细菌。消炎（药 SCD93的性质将进行研究，并将其与TM-D1进行比较。膜束缚 CD93调节体外吞噬作用和粘附，调节中的关键过程 炎症。以前已经鉴定出特定CD93细胞质尾巴的研究 相互作用的分子已知参与细胞骨架动力学，例如 吞噬作用和粘附所需的需要。本地化和功能 将评估吞噬过程中的这些分子。这些研究会 有助于我们对炎症的理解，并可能导致CD93指导 治疗以调节这一过程。