Regulation of chemoattractant receptors of the formyl peptide receptor family

甲酰肽受体（FPRs）是主要在粒细胞和单核细胞上表达的G蛋白偶联受体家族。它们通过感测原型甲酰基-Met-Leu-Phe（fMLF）的趋化性细菌肽的梯度来引导白细胞朝向细菌感染部位。最近的证据表明，FPRs也可以与许多非细菌来源的配体相互作用。其中，我们可以确定抗炎蛋白膜联蛋白1作为内源性FPR配体。膜联蛋白1最可能从炎症部位的细胞释放，可使FPR脱敏，从而阻断白细胞沿沿着fMLF梯度外渗。基于这些观察结果，我们现在想要描述膜联蛋白1介导的FPR调节的机制基础。首先，应分析内源性配体膜联蛋白1激活FPR后的细胞内信号传导，并与fMLF启动的信号传导进行比较。此外，我们想表征FPR在激动剂（膜联蛋白1/fMLF）诱导的内吞作用中的细胞内行程。第二，应鉴定受体中的膜联蛋白1结合位点。第三，最近确定的基因膜联蛋白1激活的FPR下游的作用应功能方面的特点，他们的作用，单核细胞跨内皮迁移。

Formyl peptide receptors (FPRs) are a family of G protein-coupled receptors primarily expressed on granulocytes and monocytes. They guide leukocytes towards sites of bacterial infections by sensing gradients of chemotactic bacterial peptides of the prototype formyl-Met-Leu-Phe (fMLF). Recent evidence shows that FPRs can also interact with a number of ligands of non-bacterial origin. Among these we could identify the anti-inflammatory protein annexin 1 as an endogenous FPR ligand. Annexin 1, which is most likely released from cells at sites of inflammation, can desensitize FPRs thereby blocking leukocyte extravasation along fMLF gradients. Based on these observations we now want to characterize the mechanistic basis of the annexin 1-mediated FPR regulation. First, intracellular signalling following FPR activation by the endogenous ligand annexin 1 should be analyzed and compared to that initiated by fMLF. Moreover, we want to characterize the intracellular itinerary of FPR in response to agonist (annexin 1/fMLF)-induced endocytosis. Second, the annexin 1 binding site in the receptor should be identified. Third, recently identified genes acting downstream of annexin 1-activated FPR should be characterized functionally with respect to their role in monocyte transendothelial migration.