OLIGOSACCHARIDE STRUCTURE & FUNCTION IN RECOGNITION

低聚糖结构

• 批准号: 7459343
• 负责人: JACQUES U BAENZIGER
• 金额: $ 63.56万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459343
• 关键词: Acute-Phase Reaction; Address; Asialoglycoprotein Receptor; Avidity; Bacterial Infections; Binding; Biochemical Genetics; Biological; Blood; Blood Circulation; Blood Coagulation Factor; Carbohydrates; Carrier Proteins; Cell Count; Cell surface; Cells; Coagulation Process; Complement; Condition; Diagnostic; Endothelial Cells; Equilibrium; Estrogens; Excision; Foundations; Genetic Models; Glycoproteins; Grant; Growth Factor; Hemolysis; Hormones; Host Defense; Immunoglobulins; Infection; Inflammation; Inflammatory; Injury; Knockout Mice; Ligands; Link; Liver; Mannose; Mediating; Metabolic; Methods; Molecular; Mus; Oligosaccharides; Pathologic; Patient currently pregnant; Physiological; Pituitary Gland; Plasma; Plasma Proteins; Pregnancy; Process; Production; Progress Reports; Protease Inhibitor; Protein Isoforms; Proteins; Proteomics; Public Health; Purpose; Range; Rate; Regulation; Relative (related person); Reproduction; Reproductive Biology; Role; Sepsis; Specificity; Stress; Structure; System; Therapeutic; Time; Ursidae Family; Whole Organism; bacterial resistance; base; carbohydrate structure; cytokine; in vivo; insight; macrophage; receptor; response; response to injury; septic

DESCRIPTION (provided by applicant): Over the 30 years' duration of this grant, this project has established a broad foundation for understanding the role of carbohydrate structures on glycoproteins. In this time our studies have defined 1) unique oligosaccharide structures as signatures found on specific plasma glycoproteins, 2) the mechanisms of recognition of these structures by carbohydrate-specific endocytic receptors, and 3) the functionally important in vivo biological consequences of this recognition. We have proceeded from determining at the molecular and cellular level the biologic basis of oligosaccharide recognition by these receptors, to delineating at the whole organism level the functional implications of such recognition. Our progress on how carbohydrate-specific endocytic receptor recognition systems clear particular glycoproteins from the circulation now culminates in a unique opportunity to take these studies to a new level of functional perspective. We have demonstrated by biochemical and genetic means that the Mannose/GalNAc-4-SO4-receptor (M/G4S-R) and the asialoglycoprotein-receptor (ASGP-R) mediate the respective clearance of glycoproteins that bear the N-linked oligosaccharide signatures of terminal GalNAc 4 SO4 and of terminal Sia12,6GalNAc. We have shown that the ASGP-R can bind glycoproteins bearing Sia12,6Gal. We hypothesize that glycoproteins bearing terminal Sia12,6Gal are in fact the major endogenous ligands for the ASGP-R and that the ASGP-R is a key regulator of the concentration of numerous plasma glycoproteins that have Sia12,6Gal termini. Preliminary studies support this proposed function. Our findings give a significant new functional identity to this receptor. We will now use genetic models and recently established proteomic methods to define the relative roles of the ASGP-R and M/G4S-R. We will determine how these receptors act, individually and in combination, to regulate levels of plasma glycoproteins based on their carbohydrate signatures, under physiologic as well as pathologic conditions ranging from regulation of estrogen production by pituitary glycoprotein hormones to the acute phase response to sepsis. These proposed studies utilize single and double receptor knockout mice 1) to address how production is balanced with clearance to regulate plasma levels of glycoproteins through recognition of their carbohydrate signatures, 2) to determine if perturbing this balance has an impact on biologic processes, and 3) to establish the molecular basis for generating isoforms of the M/G4S-R with differing carbohydrate signature specificities and determine the impact of such receptor isoforms on reproductive biology. The fundamental mechanistic information that we uncover will ultimately yield insights that can aid in evaluating changes in plasma proteins for both diagnostic and therapeutic purposes. Public Health Relevance: The levels of glycoproteins in the blood reflect a balance between their synthesis and removal. We have identified two major carbohydrate specific receptor systems in liver that help control the concentrations of many glycoproteins in the blood by determining their rates of removal. We will define how these receptors control the concentrations of hormones and inflammatory proteins during pregnancy and the response to injury.

描述（由申请人提供）：在该资助的 30 年期间，该项目为理解碳水化合物结构对糖蛋白的作用奠定了广泛的基础。这次我们的研究定义了 1) 独特的寡糖结构作为在特定血浆糖蛋白上发现的特征，2) 碳水化合物特异性内吞受体识别这些结构的机制，以及 3) 这种识别的功能上重要的体内生物学后果。我们从在分子和细胞水平上确定这些受体识别寡糖的生物学基础，到在整个生物体水平上描述这种识别的功能含义。我们在碳水化合物特异性内吞受体识别系统如何从循环中清除特定糖蛋白方面取得的进展现在达到了顶峰，为将这些研究提升到功能视角的新水平提供了独特的机会。我们通过生化和遗传学手段证明，甘露糖/GalNAc-4-SO4-受体（M/G4S-R）和脱唾液酸糖蛋白受体（ASGP-R）分别介导带有末端 GalNAc 4 SO4 和末端 Sia12,6GalNAc 的 N 连接寡糖特征的糖蛋白的清除。我们已经证明 ASGP-R 可以结合带有 Sia12,6Gal 的糖蛋白。我们假设带有 Sia12,6Gal 末端的糖蛋白实际上是 ASGP-R 的主要内源配体，并且 ASGP-R 是具有 Sia12,6Gal 末端的众多血浆糖蛋白浓度的关键调节剂。初步研究支持这一提议的功能。我们的研究结果为该受体提供了重要的新功能特性。我们现在将使用遗传模型和最近建立的蛋白质组学方法来定义 ASGP-R 和 M/G4S-R 的相对作用。我们将确定这些受体如何单独或组合发挥作用，在生理和病理条件下（从垂体糖蛋白激素调节雌激素产生到脓毒症急性期反应）根据其碳水化合物特征调节血浆糖蛋白水平。这些拟议的研究利用单受体和双受体敲除小鼠：1) 解决如何平衡生产与清除，通过识别碳水化合物特征来调节糖蛋白的血浆水平，2) 确定扰乱这种平衡是否对生物过程产生影响，3) 建立产生具有不同碳水化合物特征特异性的 M/G4S-R 亚型的分子基础，并确定影响 此类受体亚型在生殖生物学中的作用。我们发现的基本机制信息最终将产生见解，有助于评估血浆蛋白的变化，以用于诊断和治疗目的。 公共卫生相关性：血液中糖蛋白的水平反映了其合成和去除之间的平衡。我们已经确定了肝脏中两种主要的碳水化合物特异性受体系统，它们通过确定糖蛋白的清除率来帮助控制血液中许多糖蛋白的浓度。我们将定义这些受体如何控制怀孕期间激素和炎症蛋白的浓度以及对损伤的反应。