Siglec-F and Resolution of Allergic Inflammation

描述(申请人提供)：虽然关于过敏性炎症中炎症反应的诱导已知很多，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利用来开发治疗过敏性疾病的新型抗炎疗法。在这项建议中，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变态反应性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上高度表达，如嗜酸性粒细胞。Siglec-F受体在调节过敏反应中的功能作用是从其细胞质尾部存在的ITIM基序中提出的，这些基序参与了免疫系统中的抑制信号通路。因此，我们建议确定1)Siglec-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Siglec-F的特异性配体，这些配体可能是由上皮在体内过敏性炎症反应中产生的(顾名思义，Siglecs与表达多糖唾液酸的配体结合)，以及3)表征Siglec-8(小鼠Siglec-F的人类同源物)及其配体在人类哮喘嗜酸性炎症部位的表达。叙述性 这项建议将增加我们对Siglec-F蛋白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更好理解可能会为患有持续慢性过敏性炎症的个人开发新的治疗方法，以停止过敏性炎症反应，从而阻止持续的过敏症状。

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.