Regulatory Mechanisms of Glycoprotein Sialylation

糖蛋白唾液酸化的调控机制

• 批准号: 10152265
• 负责人: Brian A Cobb
• 金额: $ 50.92万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152265
• 关键词: ABO blood group system; Affinity; Age; Agonist; Alpha Granule; Anti-Inflammatory Agents; Antibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Back; Biological; Biology; Blood Platelets; Cells; Characteristics; Critical Pathways; Cytidine Monophosphate N-Acetylneuraminic Acid; Data; Development; Disease; Disease Progression; Disease susceptibility; Endocytosis; Environment; Enzymes; Equilibrium; Fc domain; Galactose; Generations; Glycobiology; Glycoproteins; Health; Hematopoietic; Hemostatic Agents; Homeostasis; Human; Immune; Immunity; Immunoglobulin G; Immunoglobulin Therapy; Immunologics; Inflammation; Inflammatory; Intravenous Immunoglobulins; Leukocyte Trafficking; Link; Location; Maintenance; Malignant Neoplasms; Mediating; Modeling; Modification; Molecular; Molecular Conformation; Mouse Strains; Multiple Sclerosis; Mus; N-Glycosylation Site; Nature; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Play; Polysaccharides; Process; Production; Protein Glycosylation; Publishing; Regulation; Research; Rheumatoid Arthritis; Role; Sialic Acids; Sialyltransferases; Signal Transduction; System; Testing; Therapeutic; Thrombin; Time; Transplantation; Work; base; bench to bedside; bevacizumab; cohesion; extracellular; falls; glycosylation; immunoregulation; in vivo; novel; novel therapeutics; protein degradation; receptor; sialic acid binding Ig-like lectin; sialylation; stem; sugar nucleotide; trafficking

Summary A major gap in the “bench to bedside” paradigm is the ability to harness the glycome for the development of novel therapeutics. Although decades of research in glycobiology have established glycomic changes associated with disease, almost nothing is known about how those changes arise, the functions they play in disease initiation or progression, or how the glycome is actually regulated. Based on provocative new data, we propose a transformative new model for glycomic compositional regulation of soluble secreted glycoproteins that provides a clear path for the development of the first generation of glycan-modulating therapies for a wide range of diseases. The model is based on the notion that the glycans of glycoproteins can be remodeled after release from the originating cell, and if correct, our findings will refute the glycobiology dogma in which glycomic changes are dependent upon the slow process of protein turnover and de novo synthesis to one that is highly dynamic, rapid, and specific to the immunologic environment. The proposal centers on the molecular action, regulation and necessary microenvironment for ST6Gal1 to add α2,6-linked sialic acids onto glycans with available terminal galactose residues. Our proposal also focuses upon the B cell-secreted glycoprotein/antibody IgG. This is a critical pathway to understand because ST6Gal1 is the sole enzyme that determines whether anti-inflammatory α2,6-sialyl-IgG or pro-inflammatory asialyl-IgG is produced at any given time, thereby making it a key immunomodulatory factor. In Aim 1, we will dissect the enzymatic action of ST6Gal1 from hematopoietic cells other than B cells during IgG production. In Aim 2, we will extend our studies to the microenvironment necessary to support ST6Gal1 activity in modifying IgG sialylation. Even if our model for glycoprotein glycan remodeling is limited to sialylation, such a pathway could influence immune pathways such as leukocyte trafficking, the distinction between self and non-self by siglecs, synthesis of the ABO blood groups, transplantation, IgG functionality and many others. Our findings could redefine the nature of the glycome as one under dynamic regulation that could be therapeutically harnessed via the creation of an entirely new class of glycosylation- altering drugs for the treatment of diseases ranging from inflammatory disorders and autoimmunity to cancer.

摘要 “板凳到床边”模式的一个主要差距是能够利用糖类来开发 新的治疗方法。尽管几十年的糖生物学研究已经确定了与糖代谢相关的变化 对于疾病，人们几乎不知道这些变化是如何产生的，它们在疾病启动中所起的作用 或进展，或糖糖实际上是如何被调节的。基于具有挑衅性的新数据，我们提出了一个 对可溶性分泌糖蛋白进行糖组成调节的变革性新模型，提供 为开发针对多种疾病的第一代糖链调节疗法提供了一条明确的途径 疾病。这个模型是基于这样一个概念，即糖蛋白的糖链在释放后可以被改造 如果我们的发现是正确的，我们的发现将驳斥糖生物学中血糖变化的教条。 依赖于蛋白质周转和从头合成到高度动态的缓慢过程， 快速的，特定于免疫环境的。该提案的中心是分子作用、调控 和ST6Gal1将α-2，6-连接唾液酸加到具有可用末端的多糖上所需的微环境 半乳糖残留物。我们的建议还侧重于B细胞分泌的糖蛋白/抗体免疫球蛋白。这是一个 关键途径需要了解，因为ST6Gal1是唯一决定是否抗炎的酶 α2，6-唾液酸基-Ig G或促炎唾液酸基-Ig G在任何给定时间产生，从而使其成为关键 免疫调节因子。在目标1中，我们将从造血细胞中剖析ST6Gal1的酶作用 在免疫球蛋白生成过程中，除B细胞外。在目标2中，我们将把我们的研究扩展到必要的微环境 支持ST6Gal1在修饰免疫球蛋白唾液酸化中的活性。即使我们的糖蛋白多糖重塑模型是 仅限于唾液酸化，这种途径可能会影响免疫途径，如白细胞运输、 通过Siglecs区分自体和非自体、ABO血型合成、移植、免疫球蛋白 功能和许多其他功能。我们的发现可以将糖类的性质重新定义为动态下的糖类 这种调节可以通过创造一种全新的糖基化来进行治疗- 改变治疗疾病的药物，从炎症性疾病和自身免疫到癌症。