Illuminating Galectin-3 Interactions to Disrupt Hepatic Fibrosis

项目总结 Galectin-3与未知细胞之间的非共价相互作用密切控制人肝纤维化 肝星状细胞表面糖蛋白。在这里，我们寻求开发方法来识别这些 功能性糖蛋白。然而，糖基化是一种翻译后修饰，导致 构建高度复杂和多相的糖链分子，其结构难以预测 仅基于遗传密码。尽管在糖科学方面取得了重大进展，但实现对 由多糖和GBP介导的生物事件仍然是一个重大障碍。这个问题的核心是 分析蛋白质-葡聚糖相互作用的有限分辨率。多聚糖主要显示为 与蛋白质结合，这种蛋白质-糖蛋白相互作用为随后的生物 进程。在这个应用中，我们提出了识别Galectin-3和Galectin-3之间相互作用的方法 肝星状细胞中的糖蛋白，并对这些结合导致的功能后果进行分类 人类生理、发育和疾病方面的事件。这些方法集成了各种技术 在定量质谱学、遗传学和糖组学方面。这项工作为一个关键问题提供了新的解决方案 这将为探索多糖在药物发现中的应用开辟新的机会 和生物医学。

PROJECT SUMMARY Human liver fibrosis is intimately controlled by noncovalent interactions between Galectin-3 and unknown cell surface glycoproteins on hepatic stellate cells. Here, we seek to develop methodologies to identify these functional glycoproteins. However, glycosylation is a post-translational modification that results in the construction of highly complex and heterogeneous glycan molecules whose structures are challenging to predict based on the genetic code alone. Despite significant advances in glycoscience, achieving selective control over biological events mediated by glycans and GBPs remains a significant obstacle. At the heart of this problem is the limited resolution with which protein-glycan interactions are analyzed. Glycans are largely displayed as conjugates with proteins, and such protein-glycoprotein interactions provide context for the ensuing biological process. In this application, we propose approaches to identify the interactions between Galectin-3 and glycoproteins in liver stellate cells, and to catalogue the functional consequences resulting from these binding events in the context of human physiology, development, and disease. These approaches integrate techniques in quantitative mass spectrometry, genetics, and glycomics. This work provides novel solutions to a key problem in glycoscience and will open new opportunities for the exploration of glycans for applications in drug discovery and biomedicine.