Molecular mechanisms underlying the S100A12-mediated activation of phagocytes: Interaction with cellular receptors and function as "damage associated molecular pattern" protein

S100A12 介导的吞噬细胞激活的分子机制：与细胞受体的相互作用以及作为“损伤相关分子模式”蛋白的功能

• 批准号: 174983064
• 负责人: Professor Dr. Dirk Föll
• 金额: --
• 依托单位: Klinik für Rheumatologie und klinischen Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/174983064?language=en
• 关键词: Molecular; mechanisms; underlying; S100A12; mediated

The granulocyte-specific protein S100A12 is overexpressed during inflammatory conditions and has been ascribed to the group of pro-inflammatory Damage Associated Molecular Pattern molecules (DAMPs). We have analyzed the characteristics of S100A12-binding to the pattern recognition receptor (PRR) RAGE (Receptor for Advanced Glycation End products). In our previously funded project we could demonstrate that S100A12 expression and release is rapidly induced in vitro and in vivo by inflammatory challenge. As other DAMPs have been shown to signal via Toll-like receptors (TLRs), we have performed surface plasmon resonance studies revealing binding of S100A12 to both RAGE and TLR4. To gain insight into the function of S100A12 we will now perform a global gene expression analysis of S100A12-induced responses of monocytes and compare this with LPS-induced gene expression profiles to get insights into the exact signalling pathways. We will elucidate the molecular mechanisms involved in the S100A12-induced activation of monocytes and the relative contribution of different PRRs. Cells will be used for in vitro-experiments after knock-down or overexpression of RAGE or the TLR4-complex, respectively. We will use RAGE-/- mice and also mice expressing a non-functional TLR4 for ex vivo and in vivo studies. In addition, a transgenic mouse over-expressing human S100A12 is planned.

在炎症条件下，粒细胞特异性蛋白S100A12过表达，并且已归因于促炎性损伤相关的分子模式分子（抑制）。我们已经分析了S100A12结合的特征，以对模式识别受体（PRR）RAGE（晚期糖基化最终产物的受体）分析。在我们先前资助的项目中，我们可以证明S100A12表达和释放是通过炎症挑战在体外和体内迅速诱导的。由于已显示其他潮湿通过Toll样受体（TLR）发出信号，因此我们进行了表面等离子体共振研究，揭示了S100A12与RAGE和TLR4的结合。为了深入了解S100A12的功能，我们现在将对S100A12诱导的单核细胞响应进行全局基因表达分析，并将其与LPS诱导的基因表达谱进行比较，以了解确切的信号传导途径。我们将阐明S100A12诱导的单核细胞激活和不同PRR的相对贡献所涉及的分子机制。细胞将分别用于敲击或过表达愤怒或TLR4复合物后的体外表现。我们将使用愤怒 - / - 小鼠以及表达非功能性TLR4的小鼠用于体内和体内研究。此外，计划了过表达的转基因小鼠S100A12。