Signaling pathways involved in CD44 regulation in human monocytic cells

参与人单核细胞 CD44 调节的信号通路

• 批准号: 342191-2007
• 负责人: Kumar, Ashok
• 金额: $ 2.26万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=527600
• 关键词: Signaling; pathways; involved; CD44; regulation

CD44 is a adhesion molecule present on most cell types and is responsible for binding to hyaluronic acid present in the connective tissue. Therefore, CD44 mediates cell-cell and cell-matrix interactions and plays an important role in cell migration during inflammation and cancer development. Most cells express CD44 but can bind HA. Certain inflammatory cytokines such as TNF-a and endotoxins such as lipopolysaccharides can cause modification in the structure of CD44 so that it can bind HA and increase their cell adhesion. Adhesion of CD44 with HA can also cause the production of certain molecules /growth factors, also called proinflammatory cytokines, which are responsible for causing inflammation. Therefore, binding of monocytes with T cells through CD44-HA interactions is a key pro-inflammatory event, and the upregulation of the ability of monocytes to bind HA is a key event in their participation in inflammatory responses. The results from our laboratory and others suggest that endotoxins (LPS), and several pro-inflammatory cytokines including TNF-a induce the expression of CD44 and generation of an adhesive phenotype in human monocytes. Therefore, understanding the molecular basis for the switch from a non-adhesive to adhesive phenotype has important biological consequences and merit investigation of this phenomenon. Therefore, the overall aim of this research proposal is to delineate the molecular mechanisms underlying the regulation of CD44 expression and generation of an adhesive CD44 phenotype. Specifically, we will study the role of intracellular signaling molecules such as PI3 kinase amd MAP kinases in the regulation of CD44 expression and generation of adhesive CD44 phenotype in monocytic cells following stimulation with TNF-alpha and LPS. This will be accomplished by investigating the expression of second messengers including the MAP and tyrosine kinases and the induction of various transcription factors and DNA binding proteins such as egr-1 and AP-1.

CD 44是存在于大多数细胞类型上的粘附分子，并且负责与结缔组织中存在的透明质酸结合。因此，CD 44介导细胞-细胞和细胞-基质相互作用，并在炎症和癌症发展期间的细胞迁移中起重要作用。大多数细胞表达CD 44，但可以结合HA。某些炎性细胞因子如TNF-α和内毒素如脂多糖可引起CD 44结构的改变，使得其可结合HA并增加它们的细胞粘附。CD 44与HA的粘附还可引起某些分子/生长因子的产生，也称为促炎细胞因子，其负责引起炎症。因此，单核细胞与T细胞通过CD 44-HA相互作用的结合是关键的促炎事件，并且单核细胞结合HA的能力的上调是它们参与炎症反应的关键事件。来自我们实验室和其他实验室的结果表明，内毒素（LPS）和包括TNF-α在内的几种促炎细胞因子诱导人单核细胞中CD 44的表达和粘附表型的产生。因此，了解从非粘附性表型到粘附性表型的转换的分子基础具有重要的生物学后果，并且值得对这种现象进行研究。因此，本研究的总体目标是阐明CD 44表达调控和粘附性CD 44表型产生的分子机制。具体来说，我们将研究细胞内信号分子如PI 3激酶和MAP激酶在调节CD 44表达和产生粘附性CD 44表型的单核细胞中的作用，这些细胞在TNF-α和LPS刺激后。 这将通过研究包括MAP和酪氨酸激酶在内的第二信使的表达以及各种转录因子和DNA结合蛋白（如MAP-I和AP-1）的诱导来实现。