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3-O-sulfation of heparan sulfate as a regular of protein function

硫酸乙酰肝素的 3-O-硫酸化作为蛋白质功能的调节

基本信息

批准号：
10615737
负责人：
Geert-Jan Boons
金额：
$ 45.17万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615737
关键词：
Address Anticoagulants Binding Binding Proteins Biological Biological Process Biology Blood Coagulation Factor Blood coagulation Carbohydrates Cell Adhesion Cell surface Cells Chemicals Code Collection Complement Activation Complex Deep Vein Thrombosis Disaccharides Disease Endothelial Cells Endothelium Engineering Enzymatic Biochemistry Enzymes Epitopes Extracellular Matrix Gene Family Goals Growth Factor Heparin Heparitin Sulfate Human Infection Inflammation Inflammatory Isoenzymes Lead Libraries Life Ligands Malignant Neoplasms Mammalian Cell Mediating Methodology Methods Micro Array Data Modality Modification Nerve Degeneration Oligosaccharides Polysaccharides Printing Protein Isoforms Proteins Pulmonary Embolism Recombinants Signal Transduction Signaling Protein Site Specificity Structure Structure-Activity Relationship Substrate Specificity Sulfate Surface Technology Therapeutic Thromboembolism Vascular Diseases Vertebral column cell type chemokine cytokine gain of function human disease interest mast cell morphogens pathogen prevent programs protein function recruit sulfotransferase therapeutic lead compound

项目摘要

Project summary/abstract Heparin is a highly sulfated carbohydrate produced by mast cells that is widely used as an anticoagulant to prevent deep vein thrombosis, pulmonary embolism and arterial thromboembolism. Heparan sulfate (HS) is structurally related to heparin and decorates the surface of all most all human cells. It interacts with a multitude of proteins including chemokines and cytokines; blood coagulation factors; growth factors and morphogens, proteins involved in complement activation, and cell adhesion and signaling proteins. HS has been implicated in human diseases such as vascular diseases, inflammation, infections and neurodegeneration. It has been postulated that HS encodes information by an ability to recruit proteins in a context-dependent manner. Although the “HS-sulfate code” hypothesis is conceptually appealing, little is known about the ligand specificities of HS binding proteins and the substrate specificities of HS-biosynthetic enzymes. As a result, it is not known whether isoforms of HS biosynthetic enzymes can create distinctive epitopes that in a cellular context can recruit specific HS- binding proteins. An understanding of the specificities of HS binding also offers opportunities to develop therapeutic modalities. In this program, chemical and chemo-enzymatic methodologies will be developed that will make it possible to prepare a focused library of biologically relevant HS epitopes with and without a 3-O-sulfate moiety. These compounds will be used to develop an HS-microarray to establish ligand requirement of HS-binding proteins. Compounds of interest will be further explored for their ability to interfere in the binding and cellular activation of endothelial cells. We will focus on HS-binding proteins involved in blood coagulation, inflammation and vascular disease. The established structure-activity relationships are expected to provide therapeutic lead compounds. The HS-microarray will also be used as a general platform to discover and characterize HS-binding proteins requiring a 3-O-sulfate. In addition, the synthetic compounds will be used to define substrate requirements of the various 3-O-sulfotransferases. Collectively, our studies will address the question of whether isoforms of 3-O-sulfotransferases can create distinctive epitopes that can recruit specific HS-binding proteins, to mediate various biological processes. 1

项目总结/文摘