Siglec-F and Resolution of Allergic Inflammation

描述（由申请人提供）：虽然我们对过敏性炎症中炎症反应的诱导了解甚多，但对自然下调过敏性炎症反应的内源性机制了解甚少。这些内源性反应可能被用来开发针对超敏性疾病的新型抗炎疗法。本研究拟探讨siglece - f（唾液酸结合ig -超家族凝集素- f）细胞表面受体的激活在变应性炎症中下调炎症和组织重塑反应中的作用。siglece - f在与过敏性炎症相关的细胞（如嗜酸性粒细胞）上高度表达。siglece - f受体在调节过敏反应中的功能作用，来自其细胞质尾部存在ITIM基序，已知ITIM基序参与免疫系统中的抑制性信号通路。因此，我们建议确定1)siglece - f在体内和体外发挥这种抗过敏作用的机制，2)鉴定和表征在体内过敏性炎症反应期间上皮可能产生的siglece - f特异性配体（正如它们的名字所暗示的那样，Siglecs与表达糖唾液酸的配体结合）。3)表征哮喘患者嗜酸性粒细胞炎症部位siglece -8（小鼠siglece - f的人类同源物）及其配体的表达。叙述

DESCRIPTION (provided by applicant): While much is known about the induction of the inflammatory response in allergic inflammation, far less is understood about endogenous mechanisms that naturally down- regulate allergic inflammatory responses. These endogenous responses could potentially be harnessed to develop novel anti-inflammatory therapies for hypersensitivity diseases. In this proposal we propose to investigate the role that activation of Siglec-F (Sialic acid-binding Ig-superfamily lectin-F) cell surface receptors play in down-regulating the inflammatory, and tissue remodeling response in allergic inflammation. Siglec-F is highly expressed on cells associated with allergic inflammation such as eosinophils. A functional role for Siglec-F receptors in regulating allergic responses is suggested from the presence in their cytoplasmic tails of ITIM motifs know to be involved in inhibitory signaling pathways in the immune system. We therefore propose to determine 1) the mechanisms by which Siglec-F exerts this anti-allergic effect in vivo and in vitro, and 2) identify and characterize ligands specific for Siglec-F that may be generated by epithelium during an allergic inflammatory response in vivo, (as their name implies Siglecs bind to ligands expressing the glycan sialic acid), and 3) characterize the expression of Siglec-8 (the human orthologue of mouse Siglec-F) and its ligand at sites of eosinophilic inflammation in humans with asthma. Narrative This proposal will increase our understanding of how a protein Siglec-F may stop the allergic response in a model of allergic inflammation. An improved understanding of how Siglec-F stops the allergic response may provide insight into the development of new therapies for individuals with ongoing chronic allergic inflammation to stop the allergic inflammatory response and thus stop continued allergy symptoms.