Regulatory Mechanisms of Glycoprotein Sialylation

总结 “从实验室到床边”范例中的一个主要差距是利用糖组用于开发 新疗法。虽然几十年的糖生物学研究已经建立了糖组学变化相关的 对于疾病，几乎没有人知道这些变化是如何产生的，它们在疾病发生中的作用， 或者进展，或者糖组是如何被调节的。基于挑衅性的新数据，我们提出了一个 用于可溶性分泌糖蛋白的糖组成调节的变革性新模型， 为开发第一代聚糖调节疗法提供了一条清晰的道路， 疾病该模型基于糖蛋白的聚糖在释放后可以被重构的概念 如果正确的话，我们的发现将反驳糖生物学的教条，即糖组学的变化 依赖于蛋白质周转和从头合成的缓慢过程， 快速且特异于免疫环境。该提案集中在分子作用，调节 以及ST 6 Gal 1将α 2，6-连接的唾液酸添加到具有可用末端的聚糖上所必需的微环境 半乳糖残基。我们的建议也集中在B细胞分泌的糖蛋白/抗体IgG。这是一 关键途径，因为ST 6 Gal 1是唯一的酶，决定是否抗炎 α 2，6-唾液酸-IgG或促炎性唾液酸-IgG在任何给定的时间产生，从而使其成为一个关键 免疫调节因子在目的1中，我们将剖析来自造血细胞的ST 6 Gal 1的酶促作用 而不是B细胞。在目标2中，我们将把我们的研究扩展到必要的微环境， 以支持ST 6 Gal 1修饰IgG唾液酸化的活性。即使我们的糖蛋白聚糖重塑模型 仅限于唾液酸化，这种途径可能影响免疫途径，如白细胞运输， 单克隆抗体区分自身与非自身，ABO血型合成，移植，IgG 功能和其他许多。我们的发现可以重新定义糖组的性质， 这种调节可以通过创造一种全新的糖基化来治疗- 改变用于治疗从炎症性疾病和自身免疫到癌症的疾病的药物。

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.