Enzymatic Degradation of Glycosaminoglycans

描述（由申请人提供）：糖胺聚糖（GAGs）是在真核细胞的细胞外基质（ECM）界面大量发现的复杂多糖。在理解细胞-ECM相互作用的动态性质（历史上ECM被认为是一种惰性物质，使细胞水合）在细胞和更高层次的组织和器官水平上影响表型的重要性方面已经发生了范式转变。这种模式的核心是化学异质性gag与细胞外环境中许多蛋白质之间的特定相互作用。因此，了解GAGs的结构-功能关系已成为一个重要的基础领域，并具有识别新的治疗靶点的潜力。然而，由于gag的多分散性和化学异质性，这一目标的进展在过去受到限制，这给它们的分离和表征带来了许多挑战。几年来，我们一直致力于解决这些挑战，开发用于可预测的GAGs解聚的酶工具，以解码其序列信息，以及敏感的分析技术，以准确检测和表征细胞或组织中极少量的GAGs。针对两类重要的GAGs，即HSGAGs和CSGAGs，我们已经成功地展示了我们的工具的实用性，以开发快速和强大的GAGs测序技术。在这项研究中，我们寻求扩展我们的工具的发展，以关注HSGAG和CSGAG结构-功能关系的生化和生物学方面。最后，我们寻求开发一个数据库平台来捕获和传播与GAG结构功能关系有关的信息和数据，这是GAG研究领域的一种新方法。我们相信我们的研究将真正加速理解gag -结构-功能在基础生物过程中的关系，这是一个越来越重要的研究领域。

DESCRIPTION (provided by applicant): Glycosaminoglycans (GAGs) are complex polysaccharides found in abundance at the cell-extracellular matrix (ECM) interface of eukaryotic cells. There has been a paradigm shift in understanding the importance of the dynamic nature of the cell-ECM interactions (historically the ECM was considered an inert material that hydrated the cells) in influencing phenotype at cellular and higher order tissue and organ levels. At the heart of this paradigm are the specific interactions between the chemically heterogeneous GAGs and numerous proteins in the extracellular environment. Thus, understanding the structure-function relationship of GAGs has gained importance both as a fundamental field and for its potential in identification of novel therapeutic targets. However, progress towards this goal has been limited in the past due to the polydispersity and chemical heterogeneity of GAGs that posed numerous challenges for their isolation and characterization. For several years, we have focused our efforts in addressing these challenges to develop enzymatic tools for predictable depolymerization of GAGs to decode their sequence information as well as sensitive analytical techniques to accurately detect and characterize extremely small amounts of GAGs available from cells or tissues. Focusing on the 2 important classes of GAGs viz. HSGAGs and CSGAGs we have successfully demonstrated the utility of our tools to develop rapid and robust technologies for sequencing GAGs. In this study we seek to expand on the development of our tools to focus on biochemical and biological aspects of HSGAG and CSGAG structure-function relationships. Finally, we seek to develop a database platform to capture and disseminate information and data pertaining to GAG structure function relationships which is a novel approach in the context of the GAG research area. We believe that our study would truly accelerate the progress of understanding GAG-structure-function relationships in fundamental biological processes-a research area that is gaining increasing importance.