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: 2010
• 资助国家: 加拿大
• 起止时间: 2010-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=458758
• 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.

CD44是一种存在于大多数细胞类型上的粘附分子，负责与结缔组织中的透明质酸结合。因此，CD44介导细胞-细胞和细胞-基质相互作用，并在炎症和癌症发展过程中的细胞迁移中发挥重要作用。大多数细胞表达CD44，但可以结合HA。某些炎性细胞因子，如TNF-a和内毒素，如脂多糖，可引起CD44结构的改变，使其与HA结合，增加其细胞粘附性。CD44与HA的粘附也会导致某些分子/生长因子的产生，也被称为促炎细胞因子，这是引起炎症的原因。因此，单核细胞通过CD44-HA相互作用与T细胞结合是一个关键的促炎事件，而单核细胞结合HA能力的上调是其参与炎症反应的关键事件。我们和其他实验室的结果表明，内毒素（LPS）和几种促炎细胞因子（包括TNF-a）诱导CD44的表达，并在人单核细胞中产生粘附表型。因此，了解从非粘着表型到粘着表型转换的分子基础具有重要的生物学意义，值得对这一现象进行研究。因此，本研究计划的总体目标是描述CD44表达调控和黏附CD44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PI3激酶和MAP激酶在单核细胞中受tnf - α和LPS刺激后对CD44表达和黏附CD44表型产生的调节作用。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egr-1和AP-1）的诱导来完成。