Siglec-F and Resolution of Allergic Inflammation

描述（由申请人提供）：虽然对过敏性炎症中炎症反应的诱导了解很多，但对天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利用来开发新的抗炎治疗过敏性疾病。在该提案中，我们建议研究Siglec-F（唾液酸结合Ig超家族凝集素-F）细胞表面受体的激活在下调过敏性炎症中的炎症和组织重塑反应中所起的作用。Siglec-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。Siglec-F受体在调节过敏反应中的功能作用是从其细胞质尾中存在的ITIM基序中提出的，已知ITIM基序参与免疫系统中的抑制性信号传导途径。因此，我们提出确定1）Siglec-F在体内和体外发挥这种抗过敏作用的机制，以及2）鉴定和表征可能在体内过敏性炎症反应期间由上皮产生的Siglec-F特异性配体，（顾名思义，Siglecs与表达聚糖唾液酸的配体结合），和3）表征Siglec-8（小鼠Siglec-F的人直向同源物）及其配体在患有哮喘的人的嗜酸性粒细胞炎症部位的表达。 叙事 这一提议将增加我们对蛋白质Siglec-F如何在过敏性炎症模型中阻止过敏反应的理解。对Siglec-F如何停止过敏反应的进一步了解可能有助于深入了解针对持续慢性过敏性炎症个体的新疗法的开发，以停止过敏性炎症反应，从而停止持续的过敏症状。

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.