权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Acquisition of a flash chromatography and HPLC preparative system

购置快速色谱和 HPLC 制备系统

基本信息

批准号：
10794678
负责人：
XUE-LONG SUN
金额：
$ 7.66万
依托单位：
CLEVELAND STATE UNIVERSITY
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：
2021-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10794678
关键词：
Active Sites Acute Affect Binding Sites Biological Biological Process Cell membrane Cell surface Cells Chromatography Chronic Dangerousness Data Analyses Disease Education Enzymes Excision Family Glycolipids Glycoproteins Glycoside Hydrolases Goals High Pressure Liquid Chromatography Immune Inflammatory Interleukin-6 Investigation Learning Location Lysosomes Macrophage Measures Mediating Membrane Methods Modernization Molecular Neuraminidase Pathologic Pathway interactions Pharmaceutical Preparations Pharmacological Treatment Physiological Polysaccharides Production Receptor Activation Receptor Signaling Regulation Reporting Research Research Infrastructure Sepsis Sialic Acids Signal Pathway Substrate Specificity System TLR4 gene TNF gene Techniques Testing Toll-like receptors Universities Vertebrates Western Blotting analog cell type cytokine design enzyme activity in vivo inhibitor innovation microbial mitochondrial membrane neglect novel novel strategies novel therapeutic intervention parent grant receptor skills tool undergraduate student

项目摘要

Project Summary/Abstract The goal of the parent grant is to develop effective sialidase inhibitors. Sialidases (also called neuraminidases) are glycosidases responsible for the removal of sialic acid (Sia) residues (desialylation) from glycan portions of glycocojugates. By desialylation, sialidases are able to modulate the functionality and stability of the Sia-containing molecules and are involved in both physiological and pathological pathways. Previous and our recent study indicate that lysosomal Neu1 sialidase could relocate to the cell surface of macrophages upon LPS stimulation, where it causes desialylation of TLR4 receptor, leading to TLR4 activation and subsequent production of pro-inflammatory cytokines. Dysregulation of TLR4 activation by LPS is responsible for chronic and acute inflammatory disorders that often causes dangerous disease like sepsis that still lacks specific pharmacological treatment. Sialidase inhibitors are useful tools for studying sialidase function and related mechanisms of the biological pathways. More importantly, effective sialidase inhibitors can be used as drugs to regulate the pathological pathways caused by sialidase, such as dysregulated TLR4 activation. Our recent study indicates that currently available pan sialidase inhibitor and microbial sialidase inhibitors could not inhibit mammalian sialidase effectively. Several mammalian sialidase inhibitors have been reported. However, current sialidase inhibitor design has usually focused on active-site binding, neglecting the subcellular localization of the active enzyme, therefore, they are less effective in vivo or may be even toxic as they will affect other sialidases inside of the cells. Therefore, the objective of this application is to develop location-specific inhibitor for Neu1 sialidase and define the Neu1 sialidase’s involvement in LPS/TLR4 signaling pathway, which will be accomplished by three specific aims: (1) Profile Neu1 sialidase expression and cell surface relocation in macrophages upon LPS stimulation; (2) Develop lysosome-targeting Neu1 sialidase inhibitors for effective regulating desialylation in LPS/TLR4 signaling pathway; (3) Develop cell surface-targeting Neu1 sialidase inhibitors for effective regulating desialylation in LPS/TLR4 signaling pathway. This study is innovative because it uses a novel approach that overcomes the current limitations in (a) profiling sialidase expression and relocation and (b) inhibiting sialidase at subcellular location. The proposed project is significant because it will (i) uncover specific desialylation that is critical to the LPS/TLR4 signal pathway and (ii) develop novel sialidase inhibitors for effective regulation of desialylation in LPS/TLR4 signaling pathway. Finally, this proposal will enhance the infrastructure of research and education at Cleveland State University, allowing undergraduate students to learn a broad spectrum of experimental techniques, data analysis and presentation skills used in modern scientific investigations.

项目总结/文摘