Illuminating Galectin-3 Interactions to Disrupt Hepatic Fibrosis

阐明 Galectin-3 相互作用以破坏肝纤维化

基本信息

批准号：
10416673
负责人：
Mia L Huang
金额：
$ 6.64万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2022-01-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10416673
关键词：
3-Dimensional Binding Binding Proteins Biological Biological Process Biology Catalogs Cell Surface Proteins Cell surface Chronic Complex Data Development Disease Etiology Event Extracellular Matrix Fibrosis Galactosides Galectin 3 Genetic Genetic Code Genetic Techniques Glycocalyx Glycoproteins Goals Heart Hepatic Stellate Cell Human Human body Immunoprecipitation In Situ In Vitro Intervention Knowledge Lactose Lead Ligands Liver Liver Cirrhosis Liver Fibrosis Liver diseases Mass Spectrum Analysis Mediating Membrane Glycoproteins Methodology Mission Molecular Molecular Structure Outcome Pathology Pathway interactions Phenotype Physiology Play Polysaccharides Post-Translational Protein Processing Prevention Proliferating Proteins Proteome Proteomics Protocols documentation Public Health Research Resolution Rest Role Signal Transduction Structure Techniques Therapeutic Therapeutic Intervention Time Tissues United States National Institutes of Health Work base disability drug discovery glycoproteomics glycosylation inhibitor/antagonist innovation neglect novel response restraint stellate cell

项目摘要

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.

项目概要人类肝纤维化受到 Galectin-3 和未知细胞之间非共价相互作用的密切控制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，会导致构建高度复杂且异质的聚糖分子，其结构难以预测仅基于遗传密码。尽管糖科学取得了重大进展，但实现选择性控制由聚糖和 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-聚糖相互作用的分辨率有限。聚糖主要显示为与蛋白质的缀合物，以及这种蛋白质-糖蛋白相互作用为随后的生物学提供了背景过程。在此应用中，我们提出了识别 Galectin-3 和肝星状细胞中的糖蛋白，并对这些结合产生的功能后果进行分类人类生理、发育和疾病背景下的事件。这些方法整合了技术定量质谱、遗传学和糖组学。这项工作为关键问题提供了新颖的解决方案糖科学领域的研究将为探索聚糖在药物发现中的应用开辟新的机会和生物医学。