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Heparan Sulfate 3-O-Sulfation in Transcellular Propagation of Tauopathy in Alzheimer's Disease

硫酸乙酰肝素 3-O-硫酸化在阿尔茨海默氏病 Tau 蛋白病跨细胞传播中的作用

基本信息

批准号：
10054740
负责人：
ROBERT J LINHARDT
金额：
$ 259.51万
依托单位：
RENSSELAER POLYTECHNIC INSTITUTE
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：
2020-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054740
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease therapy Animal Model Animals Binding Biosensor Brain Cell Culture Techniques Cell Line Cell surface Cells Chemicals Clustered Regularly Interspaced Short Palindromic Repeats Complex Core Protein Data Dementia Disaccharides Disease Drug Design Enzymes Fluorescence Resonance Energy Transfer Future Glucosamine Glucuronic Acids Goals Heparan Sulfate Proteoglycan Heparitin Sulfate Hippocampus (Brain)Human Iduronic Acid Impaired cognition Injections Link MAPT gene Mass Spectrum Analysis Mediating Methods Microtubule Stabilization Microtubules Modification Molecular Movement Mutagenesis Neurofibrillary Tangles Neurons Oligosaccharides Pathogenesis Pathologic Pathology Pattern Pharmaceutical Preparations Physiology Play Polysaccharides Proteins Public Health Relaxation Role Signal Transduction Small Interfering RNA Staging Structure Sulfate Surface Tauopathies Testing Translating Uronic Acids Work base cell type design drug development drug discovery hTau Mice inhibitor/antagonist insight migration mimetics molecular dynamics mouse genetics mouse model neural network novel overexpression prion-like protein aggregation role model structural biology sulfotransferase tau Proteins tau aggregation tau interaction tool uptake

项目摘要

Neurofibrillary tangles (NFT) is a pathological hallmark of Alzheimer’s disease (AD). NFT is composed of aggregated tau protein and is correlated to cognitive decline in dementia progression. NFT spreads in the brain in a prion-like manner, mediated by the interaction between tau and neuronal surface glycans. The long-term goal is to study the structural details of tau-glycan interaction and to discover drugs to disrupt this interaction for disease-modifying treatment of AD. In this proposal, we will study the tau-heparan sulfate interaction from at the molecular (aim 1), the cellular (aim 2), and organismal level and carry out drug discovery (aim 3).

神经原纤维缠结（NFT）是阿尔茨海默病（AD）的病理标志。 NFT 由聚集的 tau 蛋白，与痴呆进展中的认知能力下降相关。 NFT 在大脑中传播以类似朊病毒的方式，由 tau 蛋白和神经元表面聚糖之间的相互作用介导。长期来看目标是研究 tau 聚糖相互作用的结构细节并发现破坏这种相互作用的药物用于 AD 的疾病缓解治疗。在本提案中，我们将研究 tau-硫酸乙酰肝素的相互作用在分子（目标 1）、细胞（目标 2）和有机体水平上进行药物发现（目标 3）。