Molecular dissection of siglec-mediated regulation of neutrophil inflammatory responses. (360G-Wellcome-103744_Z_14_Z)

Regulation of neutrophil-endothelial cell interactions and entry into the lung is important in preventing acute lung injury during sepsis. Our recent work has identified a new siglec (sialic acid binding Ig-like lectin) inhibitory pathway that controls beta2 integrin dependent neutrophil recruitment to the lung following exposure to lipolysaccharide. The overall goal of the proposed research is to understand in molecular detail how the neutrophil-expressed siglecs in mice (siglec-E) and humans ( siglec-9 and paired receptors siglec-5/14) regulate neutrophil functions during inflammation.This will be achieved through detailed proteomic and glycomic analyses of (i) siglec signalling complexes and (ii) siglec counterreceptors and ligands on lung microvascular endothelial cells. The specific questions are: 1. How does siglec-E control neutrophil signalling? 2. What are the siglec-E glycan ligands and glycoprotein counter-receptors expressed on lung capillary endothelial cells? 3 . How are human neutrophil siglecs-9 and -5/14 organised into discrete microdomains on the neutrophil surface and what are their respective biological functions? What is the nature of siglec-9 and siglec-5/14 cis binding partners on neutrophils?