Function of the haematopoietic GTPase RhoH in mast cell signalling

RhoH是Rho蛋白家族中一种造血特异性的、GTP酶缺乏的成员，它作为JAK-STAT和NFκB信号的调节因子。我们最近发现，RhoH控制着特定的Toll样受体(TLRs)的表达水平，TLRs是先天免疫系统中微生物成分的传感器。RhoH的表达水平影响TLR介导的巨噬细胞释放炎性细胞因子，通过这一途径和其他迄今尚未明确的途径。众所周知，RhoH对涉及Syk、STATS、NFkB和其他Rho GTP酶的信号通路有影响。然而，人们对这些信号通路的确切分子机制知之甚少。我们的目标是在分子水平上了解RhoH介导的蛋白质转运和TLR信号转导的机制。作为模型系统，我们将使用来自野生型和RhoH缺陷小鼠的骨髓来源的巨噬细胞。我们预计结果将是重要的，以便定义可能允许操纵免疫细胞实现其所需的有益功能的机制。该项目将研究TLR诱导的免疫信号转导过程的调节，通过RhoH导致细胞因子的释放和细胞功能，如吞噬。

RhoH is a haematopoiesis specific, GTPase-deficient member of the family of Rho proteins that acts as a regulator of JAK-STAT and NFκB signalling. We recently found that RhoH controls the expression levels of specific Toll like receptors (TLRs) that act as sensors of microbial components in the innate immune system. By this and other, so far uncharacterised pathways, RhoH expression levels influence TLR-mediated release of inflammatory cytokines from macrophages. It is known that RhoH has an impact on the signalling pathways involving Syk, STATs, NFkB and other Rho GTPases. However, very little is known about the exact molecular mechanisms of these signalling pathways. We aim to understand the mechanism of RhoH-mediated modulation of protein transport and TLR signalling on a molecular level. As a model system we will use bone marrow derived macrophages from wildtype and RhoHdeficient mice. We anticipate the results to be important in order to define mechanisms that might allow manipulating immune cells towards their desired, beneficial function. The project will investigate the regulation of TLR-induced immune signal transduction processes through RhoH leading to cytokine release and cellular functions such as phagocytosis.