A Research Program on Advancing Biomedical Glycoproteomics

项目摘要/摘要 与疾病相关的蛋白质糖基化改变的生物医学相关性已被公认为 过段时间吧。然而，在将这些观察结果转化为强大的疾病方面仍然存在重大挑战。 生物标志物，以及建立对改变的蛋白质糖基化如何影响的详细分子理解 各种各样的生物分子相互作用和蛋白质结构/功能的相互作用。因为蛋白质 糖基化是复杂的非模板生物合成过程的最终结果，这是一种蛋白质糖型 对代谢异常非常敏感，包括那些伴随疾病而来的代谢异常。出于这些原因， 蛋白质糖基化的详细分子特征在生物医学领域具有重要意义。 疾病生物标志物的发现，以及与疾病引起的蛋白质糖基化改变相关的目的 对蛋白质的作用。这种努力的关键是强大的分析技术，这些技术可以确定 蛋白质连接的多聚糖的组成和结构及其在复合体和复合体中的蛋白质附着位置 非均质混合物。这项对Mira计划的申请要求支持一个研究计划 致力于通过生物医学糖蛋白组学的开发、应用和 基于质谱学、串联质谱学和离子迁移率光谱学的工具的传播 询问糖蛋白质组并确定特定部位的蛋白质糖形式。这项计划的目标是 与国家卫生研究院目前的优先事项一致，包括最近呼吁在早期阶段增加投资 开发生物医学研究的新技术和正在进行的举措，以促进 糖科学。这项工作将产生的新技术将是可推广的，因此适用于 在一个折衷的生物医学相关的背景下阐明特定部位的蛋白质糖形模式。

PROJECT SUMMARY / ABSTRACT The biomedical relevance of disease-related alterations in protein glycosylation has been recognized for some time. However, significant challenges remain in translating these observations into robust disease biomarkers, and in establishing a detailed molecular understanding of how altered protein glycosylation affects a diverse variety of biomolecular interactions and protein structure / function interplays. Because protein glycosylation is the end result of complex non-template-driven biosynthetic processes, a protein glycoform profile is exquisitely sensitive to metabolic irregularities, including those that accompany disease. For these reasons, the detailed molecular characterization of protein glycosylation is of great biomedical interest in the context of disease biomarker discovery, and for the purpose of relating disease-induced alterations of protein glycosylation to protein function. Essential to such endeavors are powerful analytical techniques that can determine the compositions and structures of protein-linked glycans and their sites of protein attachment in complex and heterogeneous mixtures. This application to the MIRA program requests support of a research program dedicated to the advancement of biomedical glycoproteomics through the development, application, and dissemination of mass spectrometry, tandem mass spectrometry, and ion mobility spectrometry based tools for interrogating the glycoproteome and determining site-specific protein glycoforms. The goals of this program are consonant with current NIH priorities, including the recent calls for increased investment in early stage development of new technologies for biomedical research and ongoing initiatives to catalyze advancements in glycoscience. The new technologies that will result from this work will be generalizable and thus applicable to the elucidation of site-specific protein glycoform patterns in an eclectic array of biomedically-relevant contexts.