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Dissecting the role of tau glycosylation in Alzheimer's disease

剖析 tau 糖基化在阿尔茨海默病中的作用

基本信息

批准号：
10662150
负责人：
Maciej Walczak
金额：
$ 203.11万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662150
关键词：
Acetylation Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Amino Acid Sequence Behavior Biochemical Biological Assay Biological Process Biology Biophysics Brain Cells Charge Chemicals Code Complex Data Dementia Development Glycoproteins Goals Human In Vitro Induced pluripotent stem cell derived neurons Interneurons K-18 conjugate Knowledge Lectin Link Liquid substance Location Lysine MAPT gene Mannose Maryland Modification Molecular Molecular Biology Molecular Conformation Monosaccharides N-Glycosylation Site Nerve Degeneration Neurodegenerative Disorders Neurons Pathologic Peptide N-glycohydrolase F Phase Phosphorylation Physical condensation Physiological Polysaccharides Positioning Attribute Post-Translational Protein Processing Protein Dephosphorylation Protein Glycosylation Protein Isoforms Proteins Reporting Role Route Sampling Site Stains Structure Testing Toxic effect Tubulin Universities biophysical properties design diagnostic strategy glycosylation hyperphosphorylated tau induced pluripotent stem cell mutant novel diagnostics novel therapeutic intervention novel therapeutics protein function response structural biology tau Proteins tau aggregation tau function tau-1 tool uptake

项目摘要

Multiple neurodegenerative conditions including Alzheimer’s disease (AD) are characterized by the accumulation of in the brain. Tau is a heavily modified protein, and SUMMARY. Microtubule-Associated Protein Tau (MAPT) specific to glycosylation, it has been found to be N-glycosylated in AD samples but not in healthy controls. Three N-glycosylation sites were identified in hTau40, but the exact impact of glycosylation on biophysical properties and cellular uptake is poorly understood. In this proposal, we aim to understand how the structure, topology, and location of glycans impact biological functions of Tau. Based on the preliminary data presented in this application, we will pursue the following three aims: In Aim 1, we will study the effects on N-glycosylation together with other modifications modulating the phase behavior of Tau. In Aim 2, we will study synergistic and antagonistic effects of Tau glycosylation and other posttranslational modifications. In Aim 3, we will investigate cellular uptake, toxicity, and stability of Tau glycoproteins in hiPSC-derived neurons. Taken together, this project will address an important knowledge gap regarding the role of glycans and enable the design of novel therapeutic and diagnostic strategies.

包括阿尔茨海默病（AD）在内的多种神经退行性病症的特征在于：在大脑中的积累。Tau是一种高度修饰的蛋白质，和摘要微管相关蛋白Tau（MAPT）对于糖基化，已经发现其在AD样品中是N-糖基化的，但在健康对照中不是。在hTau 40中鉴定了三个N-糖基化位点，但糖基化对生物物理学的确切影响尚不清楚。性质和细胞摄取知之甚少。在这个建议中，我们的目标是了解结构，拓扑结构和聚糖的位置影响Tau的生物学功能。根据第2004/2005号文件中提供的初步数据，在本申请中，我们将追求以下三个目标：在目标1中，我们将研究对N-糖基化的影响以及调节Tau相行为的其它修饰。在目标2中，我们将研究协同和 Tau糖基化和其他翻译后修饰的拮抗作用。在目标3中，我们将研究在hiPSC衍生的神经元中Tau糖蛋白的细胞摄取、毒性和稳定性。总体而言，该项目将解决关于聚糖作用的重要知识缺口，并使设计新的治疗药物成为可能。诊断策略。