Protein-glycan Interactions in the Vascular System

描述(由申请人提供)： 该计划项目资助计划采用跨学科的方法来研究蛋白质多糖相互作用在血管系统中的功能。这三个主题相关的项目由研究人员领导，他们具有互补的专业知识和良好的合作研究出版记录。项目1使用基因靶向的小鼠来研究血管系统中黏附分子和信号分子的相互作用。重点是调节选择素与其糖共轭配体的相互作用的过程，这是炎症和血栓形成过程中的关键早期反应。将对选择素、选择素配体或糖基转移酶表达改变的小鼠进行研究。项目2研究了Galectins(另一类凝集素)与中性粒细胞的相互作用。Galectins，其中一些在血管内皮细胞中表达，诱导激活的中性粒细胞上的磷脂酰丝氨酸暴露，而不会导致细胞凋亡。这代表了一种清除炎症部位激活的中性粒细胞的新机制，将在该提案中进一步探索。项目3研究核心1衍生的O-葡聚糖如何促进血管生成。主要工具是组织特异性或诱导缺失编码T-合酶的基因的小鼠，T-合酶是一种糖基转移酶，构成所有核心10-糖聚糖的前体。由于知识上的重叠主题以及试剂和方法的共享，这些项目之间具有不同寻常的高度协同效应。管理核心巩固了相互作用，特别是通过维护用于在项目之间交换数据的服务器以及通过计算机支持处理图像和其他复杂数据。所获得的数据将加深我们对凝集素和糖结合物在炎症、血栓形成和血管生成过程中在血管系统中的作用的理解。这些信息可能会建议治疗心脏病发作、中风和其他心血管疾病的新方法。

DESCRIPTION (provided by applicant): This Program Project Grant proposal employs an interdisciplinary approach to study the functions of protein glycan interactions in the vascular system. The three thematically related projects are led by investigators with complementary expertise and a strong published record of collaborative research. Project 1 uses gene targeted mice to study the interplay of adhesion and signaling molecules in the vasculature. The emphasis is on processes that regulate the interactions of selectins with their glycoconjugate ligands, a critical early response during inflammation and thrombosis. Mice with altered expression of selectins, selectin ligands, or glycosyltransferases will be studied. Project 2 studies the interactions of galectins, another class of lectins, with neutrophils. The galectins, some of which are expressed in vascular endothelial cells, induce exposure of phosphatidylserine on activated neutrophils without causing apoptosis. This represents a novel mechanism for clearing activated neutrophils at sites of inflammation that will be explored further in the proposal. Project 3 studies how core 1-derived O-glycans contribute to angiogenesis. Major tools are mice with tissue-specific or inducible deletions of the gene encoding T-synthase, a glycosyltransferase that constructs the precursor for all core 1 O-glycans. There is unusually high synergy among the projects that results from the intellectually overlapping themes and the sharing of reagents and methods. An administrative core cements the interactions, in particular through maintenance of a server for data exchange among the projects and through computer support for processing images and other complex data. The data obtained will enhance our understanding of the functions of lectins and glycoconjugates in the vascular system during inflammation, thrombosis, and angiogenesis. This information may suggest new approaches to treat heart attacks, strokes, and other cardiovascular disorders.