Regulated expression of siglec counter-receptors

炎症性白细胞的浸润和活化驱动哮喘和慢性支气管炎的病理生理学 阻塞性肺疾病（COPD），两种肺部炎症性疾病（LID）， 并消耗大量医疗资源。嗜酸性粒细胞和中性粒细胞表达 聚糖结合蛋白的siglec家族的不同成员，以及任一细胞上的siglec活化 人群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 中性粒细胞表达Siglec-8，中性粒细胞表达Siglec-9。结合这些单克隆抗体的候选配体是 通过体外聚糖阵列筛选鉴定，预测预期的关键结构特征， 有效的内源性siglec反受体。然而，Siglec-8的内源性聚糖反受体 和-9，以及它们所连接的蛋白质或脂质仍有待确定。此外，委员会认为， 控制SigleC反受体表达的机制尚不清楚，但是，如果理解， 可以通过增强的反受体合成来促进粒细胞凋亡。 假设：内源性siglec反受体的表达受先天性信号传导调节 协调强效促炎和抗炎聚糖呈递的机制。AIMS：The 人肺组织和分离的细胞类型的总糖组将通过质谱法表征， 正交分析方法来确定潜在的siglec反受体的全部多样性 配置.与Proiect 3（Schnaar）合作，亲和纯化材料的蛋白质组学分析 从人肺组织中提取的蛋白质将鉴定呈递SigleC反受体的蛋白质载体。 新出现的证据揭示了siglec和toll样受体信号传导之间的串扰，表明 存在用于控制聚糖表达的先天调节网络。因此， 细胞特异性聚糖表达将在细胞因子或Toll样受体激动剂 施用至分离的和共培养的肺细胞类型。目标旨在确定 内源性反受体的siglecs和去卷积的信号转导途径，调节 反受体表达，以增强有效治疗剂的开发。 相关性（参见说明）： 这个项目将确定在肺部炎症中具有抗炎活性的聚糖结构， 哮喘和慢性阻塞性肺疾病等LID。肺的机制 组织和白细胞通常控制这些抗炎聚糖的合成也将被研究 以提高它们的产量，从而降低LID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.