Regulated expression of siglec counter-receptors

炎性白细胞的浸润和激活在哮喘和慢性阻塞性肺疾病的病理生理机制中的作用 阻塞性肺疾病(COPD)，两种肺部炎症性疾病(LID) 人类痛苦和消耗相当大的医疗资源。嗜酸性粒细胞和中性粒细胞表达 Siglec家族的不同成员的糖链结合蛋白，以及Siglec在任一细胞上的激活 Popular通过诱导粒细胞凋亡抑制肺部炎症。在人类中，嗜酸性粒细胞 表达Siglec-8，中性粒细胞表达Siglec-9。与这些印记结合的候选配体是 通过体外多糖阵列筛选鉴定，预测预期的关键结构特征 强大的内源性Siglec抗受体。然而，内源性多糖对Siglec-8受体的拮抗作用 和-9，以及它们附着的蛋白质或脂类仍有待确定。此外， 控制Siglec反式受体表达的机制尚不清楚，但如果了解， 可通过增强的抗受体合成促进粒细胞的凋亡。 假设：内源性Siglec受体的表达受先天信号调节 协调有效的促炎和抗炎多聚糖的呈递机制。目标： 人肺组织和分离的细胞类型的总糖将通过质谱学和 确定潜在Siglec拮抗受体全多样性的正交分析方法 配置。与项目3(Schnaar)合作，亲和纯化材料的蛋白质组学分析 从人类肺组织中提取的蛋白质将识别出呈现Siglec反受体的蛋白质载体。 新的证据显示，Siglec和Toll样受体信号之间存在串扰，表明 存在控制多糖表达的固有调控网络。因此，动态变化在 使用细胞因子或Toll样受体激动剂后将评估细胞特异性糖链的表达 给药至分离和共培养的肺细胞类型。这些目标旨在确定 Siglecs的内源性对抗性受体和解旋调节信号通路 反式受体的表达，以促进有效治疗药物的开发。 相关性(请参阅说明)： 该项目将确定在肺部炎症中具有抗炎活性的多糖结构。 疾病(LID)，如哮喘和慢性阻塞性肺病。肺的作用机制 组织和白细胞通常控制这些抗炎多糖的合成，也将进行研究 以提高它们的产量，从而降低盖子的严重性。

Infiltration and activation of inflammatory leukocytes drive the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD), two lung inflammatory diseases (LIDs) that produce signiflcant human suffering and consume considerable medical resources. Eosinophils and neutrophils express different members of the siglec family of glycan binding proteins, and siglec activation on either cell population suppresses lung inflammation by inducing granulocyte apoptosis. In humans, eosinophils express Siglec-8 and neutrophils express Siglec-9. Candidate ligands that bind these siglecs were identified through in vitro glycan array screening, predicting key structural features to be expected of potent, endogenous siglec counter-receptors. However, endogenous glycan counter-receptors for Siglec-8 and -9, as well as the proteins or lipids to which they are attached remain to be determined. Furthermore, the mechanisms that control the expression of siglec counter-receptors are unknown, but, if understood, could be invoked to facilitate granulocyte apoptosis through enhanced counter-receptor synthesis. HYPOTHESIS: The expression of endogenous siglec counter-receptors is regulated by innate signaling mechanisms that coordinate the presentation of potent pro- and anti-infiammatory glycans. AIMS: The total glycome of human lung tissue and isolated cell types will be characterized by mass spectrometry and orthogonal analytic approaches to define the full diversity of potential siglec counter-receptor configurations. In collaboration with Proiect 3 (Schnaar), proteomic analysis of affinity-purified materials extracted from human lung tissue will identify protein carriers that present siglec counter-receptors. Emerging evidence reveals crosstalk between siglec and toll-like receptor signaling, indicating the existence of innate regulatory networks for controlling glycan expression. Therefore, dynamic changes in cell-specific glycan expression will be assessed following cytokine or Toll-like receptor agonist administration to isolated and co-cultured lung cell types. The aims are designed to identify the diversity of endogenous counter-receptors for siglecs and to deconvolute the signaling pathways that regulate counter-receptor expression in order to enhance the development of potent therapeutics. RELEVANCE (See instructions): This project will identify glycan structures that possess anti-inflammatory activity in lung inflammatory diseases (LID) such as asthma and chronic obstructive pulmonary disease. The mechanism by which lung tissue and leukocytes normally control the synthesis of these anti-inflammatory glycans will also be studied in order to enhance their production and thereby reduce LID severity.