Evaluation and Disruption of Tau - GSK3β Vicious Cycle

Tau 的评估和破坏 - GSK3β 恶性循环

• 批准号: 10398663
• 负责人: Daniel Gulbranson
• 金额: $ 0.25万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398663
• 关键词: Adult; Adverse effects; Alzheimer' s Disease; Alzheimer' s disease model; Antisense Oligonucleotides; Axonal Transport; Binding; Blood - brain barrier anatomy; Brain; Cells; Data; Development; Disease; Disease Progression; Dose; Enterobacteria phage P1 Cre recombinase; Evaluation; Excision; Exposure to; Goals; Human; Immune; Impaired cognition; Knockout Mice; Lead; Learning; Maintenance; Mediating; Memory; Memory impairment; Modeling; Mus; Nerve Degeneration; Neuroglia; Neurons; Pathogenesis; Pathogenicity; Pathway interactions; Penetration; Phosphotransferases; Preclinical Testing; Process; Protein Kinase; Proteins; Safety; Signal Transduction; Tauopathies; Testing; Therapeutic; Transgenic Organisms; Viral Vector; excitatory neuron; excitotoxicity; experimental study; in vivo; mouse model; mutant; neuron loss; neuronal survival; offspring; prevent; promoter; protein kinase inhibitor; rho; tau Proteins; tau expression; tau mutation

Project Summary/Abstract Our goal is to advance our understanding and ability to treat Alzheimer's disease. Our lab discovered that tau reduction can prevent A-induced activation of GSK3, a kinase that is activated by many AD-relevant pathomechanisms and has been implicated in the hyperphosphorylation of tau. We will determine which of these mechanisms activate GSK3β in a tau-dependent manner and whether the activation involves direct interactions between tau and GSK3β. To prevent tau-dependent GSK3 activation, we propose to reduce overall tau levels. Tau reduction can prevent cognitive decline and neurodegeneration in mouse models of AD. We found that blocking the rho-associated protein kinase (ROCK) pathway reduces tau levels in primary cells and in adult mouse brain. To further explore this therapeutic strategy, we will use a new ROCK inhibitor that has high potency and good brain penetration in mouse models.

项目总结/文摘

项目成果

Generating Custom Pooled CRISPR Libraries for Genetic Dissection of Biological Pathways.

生成用于生物途径遗传解析的定制 CRISPR 文库。

• DOI: 10.1007/978-1-0716-2209-4_21
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Gulbranson,DanielR