Protein-glycan Interactions in the Vascular System

描述（由申请人提供）： 本计画计画补助金提案采用跨学科的方法来研究血管系统中蛋白质聚糖相互作用的功能。这三个主题相关的项目由具有互补专业知识和强大的合作研究记录的研究人员领导。项目1使用基因靶向小鼠研究血管系统中粘附和信号分子的相互作用。重点是调节选择素与其糖缀合物配体的相互作用的过程，这是炎症和血栓形成期间的关键早期反应。将研究选择素、选择素配体或糖基转移酶表达改变的小鼠。项目2研究半乳糖凝集素（另一类凝集素）与中性粒细胞的相互作用。半乳糖凝集素，其中一些在血管内皮细胞中表达，诱导活化的中性粒细胞上的磷脂酰丝氨酸暴露而不引起细胞凋亡。这代表了在炎症部位清除活化中性粒细胞的一种新机制，将在提案中进一步探讨。项目3研究核心1衍生的O-聚糖如何促进血管生成。主要工具是具有编码T-合酶的基因的组织特异性或诱导性缺失的小鼠，T-合酶是一种构建所有核心10-聚糖的前体的糖基转移酶。由于知识上的重叠主题以及试剂和方法的共享，这些项目之间具有异常高的协同作用。一个行政核心加强互动，特别是通过维护一个服务器，用于项目之间的数据交换，并通过计算机支持处理图像和其他复杂数据。所获得的数据将增强我们对凝集素和糖缀合物在炎症、血栓形成和血管生成过程中在血管系统中的功能的理解。这一信息可能为治疗心脏病发作、中风和其他心血管疾病提供新的方法。

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.