Dual CHIP Functions Control Tau Triage In Alzheimer's Disease

双芯片功能控制阿尔茨海默氏病的 Tau 分类

基本信息

  • 批准号:
    10319914
  • 负责人:
  • 金额:
    $ 61.97万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-03-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT The accumulation of aggregated tau protein in the brain is a defining feature of Alzheimer’s disease (AD) and a logical therapeutic target to prevent AD progression. Genetic evidence in mice strongly supports the notion that tau promotes cognitive deficits in AD. While anti-aggregation and immunotherapy approaches have emerged as potential strategies to reduce tau aggregation in the brain, these target late-stage tau intermediates. Much less is known about the early-stage events that give rise to tau aggregates in otherwise healthy neurons, a time period in which chaperone-dependent refolding acts in a compensatory manner to restore tau function as a critical microtubule (MT) stabilizing factor. We seek to define these early-stage tau triage decisions since clinically targeting tau in this earlier window is highly desirable to prevent tau accumulation, particularly in asymptomatic individuals years to decades from disease onset. The C-terminus of heat shock 70-interacting protein (or CHIP) plays a central role in orchestrating protein quality control. While most prior studies have pointed to CHIP’s E3 ligase activity as a principal mediator of client substrate degradation including tau, studies now indicate that CHIP contains a poorly understood intrinsic chaperone function that operates completely independent of its E3 ligase activity. Genetic studies of spinocerebellar ataxia 16 (SCAR 16) patients, a rare neurodegenerative disorder, showed that loss of CHIP co-chaperone activity alone is sufficient to cause neurodegeneration and cognitive dysfunction. These prior studies, combined with our compelling new preliminary data showing that CHIP directly binds and chaperones tau to facilitate its dephosphorylation, provide strong support for a new model of CHIP-mediated tau triage. We hypothesize that CHIP prevents aberrant tau modifications and aggregation, restores normal tau function and MT stabilization, and ameliorates AD-related cognitive decline. In Aim-1, we will dissect CHIP’s dual functions as a regulator of tau function and phosphorylation using biochemical and biophysical assays in vitro. These studies will provide new mechanistic insights into how CHIP targets and repairs abnormal tau species. In Aim-2, we will explore a novel role for CHIP in mediating neuroprotection via the stabilization of MTs. We will test the requirements for CHIP co-chaperone activity in maintaining MT integrity and hence promoting survival in neurons that would otherwise undergo degeneration. Finally, in Aim-3, we will test the clinical implications of CHIP co-chaperone function in restoring cognition in an animal model of AD. Overall, our proposal is significant because it will illuminate the early-stage events that determine how tau is initially processed and triaged. It is also innovative because it is the first to highlight dual molecular functions of CHIP that are relevant to tau pathogenesis and the progression of this devastating disease.
项目总结/文摘

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Todd Jonathan Cohen其他文献

Todd Jonathan Cohen的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Todd Jonathan Cohen', 18)}}的其他基金

Identifying kinase signaling pathways linked to tau-mediated neurodegeneration
识别与 tau 介导的神经变性相关的激酶信号通路
  • 批准号:
    10753257
  • 财政年份:
    2023
  • 资助金额:
    $ 61.97万
  • 项目类别:
CRISPR gene therapies targeting tau in Alzheimer's disease and tauopathies
针对阿尔茨海默病和 tau 病中 tau 蛋白的 CRISPR 基因疗法
  • 批准号:
    10752745
  • 财政年份:
    2023
  • 资助金额:
    $ 61.97万
  • 项目类别:
Sleep-dependent synaptic homeostasis in Alzheimer's disease
阿尔茨海默病中睡眠依赖性突触稳态
  • 批准号:
    10209327
  • 财政年份:
    2021
  • 资助金额:
    $ 61.97万
  • 项目类别:
Identifying Alzheimer’s Disease Causal Variants and Target Genes Using iPSC-derived Microglia
使用 iPSC 衍生的小胶质细胞识别阿尔茨海默病致病变异和靶基因
  • 批准号:
    10382389
  • 财政年份:
    2020
  • 资助金额:
    $ 61.97万
  • 项目类别:
Identifying Alzheimer’s Disease Causal Variants and Target Genes Using iPSC-derived Microglia
使用 iPSC 衍生的小胶质细胞识别阿尔茨海默病致病变异和靶基因
  • 批准号:
    10615602
  • 财政年份:
    2020
  • 资助金额:
    $ 61.97万
  • 项目类别:
Dual CHIP Functions Control Tau Triage In Alzheimer's Disease
双芯片功能控制阿尔茨海默氏病的 Tau 分类
  • 批准号:
    10088361
  • 财政年份:
    2019
  • 资助金额:
    $ 61.97万
  • 项目类别:
Dual CHIP Functions Control Tau Triage In Alzheimer's Disease
双芯片功能控制阿尔茨海默氏病的 Tau 分类
  • 批准号:
    10539271
  • 财政年份:
    2019
  • 资助金额:
    $ 61.97万
  • 项目类别:
Elucidating The Aberrant TDP-43 Species That Promote Neurodegeneration
阐明促进神经退行性变的异常 TDP-43 物种
  • 批准号:
    10385722
  • 财政年份:
    2018
  • 资助金额:
    $ 61.97万
  • 项目类别:
TDP-43 acetylation as a pathogenic modification in ALS & related proteinopathies
TDP-43 乙酰化作为 ALS 的致病修饰
  • 批准号:
    8849550
  • 财政年份:
    2014
  • 资助金额:
    $ 61.97万
  • 项目类别:
TDP-43 acetylation as a pathogenic modification in ALS & related proteinopathies
TDP-43 乙酰化作为 ALS 的致病修饰
  • 批准号:
    8862550
  • 财政年份:
    2014
  • 资助金额:
    $ 61.97万
  • 项目类别:

相似国自然基金

新型F-18标记香豆素衍生物PET探针的研制及靶向Alzheimer's Disease 斑块显像研究
  • 批准号:
    81000622
  • 批准年份:
    2010
  • 资助金额:
    20.0 万元
  • 项目类别:
    青年科学基金项目
阿尔茨海默病(Alzheimer's disease,AD)动物模型构建的分子机理研究
  • 批准号:
    31060293
  • 批准年份:
    2010
  • 资助金额:
    26.0 万元
  • 项目类别:
    地区科学基金项目
跨膜转运蛋白21(TMP21)对引起阿尔茨海默病(Alzheimer'S Disease)的γ分泌酶的作用研究
  • 批准号:
    30960334
  • 批准年份:
    2009
  • 资助金额:
    22.0 万元
  • 项目类别:
    地区科学基金项目

相似海外基金

Pathophysiological mechanisms of hypoperfusion in mouse models of Alzheimer?s disease and small vessel disease
阿尔茨海默病和小血管疾病小鼠模型低灌注的病理生理机制
  • 批准号:
    10657993
  • 财政年份:
    2023
  • 资助金额:
    $ 61.97万
  • 项目类别:
Social Connectedness and Communication in Parents with Huntington''s Disease and their Offspring: Associations with Psychological and Disease Progression
患有亨廷顿病的父母及其后代的社会联系和沟通:与心理和疾病进展的关联
  • 批准号:
    10381163
  • 财政年份:
    2022
  • 资助金额:
    $ 61.97万
  • 项目类别:
The Role of Menopause-Driven DNA Damage and Epigenetic Dysregulation in Alzheimer s Disease
更年期驱动的 DNA 损伤和表观遗传失调在阿尔茨海默病中的作用
  • 批准号:
    10531959
  • 财政年份:
    2022
  • 资助金额:
    $ 61.97万
  • 项目类别:
The Role of Menopause-Driven DNA Damage and Epigenetic Dysregulation in Alzheimer s Disease
更年期驱动的 DNA 损伤和表观遗传失调在阿尔茨海默病中的作用
  • 批准号:
    10700991
  • 财政年份:
    2022
  • 资助金额:
    $ 61.97万
  • 项目类别:
Interneurons as early drivers of Huntington´s disease progression
中间神经元是亨廷顿病进展的早期驱动因素
  • 批准号:
    10518582
  • 财政年份:
    2022
  • 资助金额:
    $ 61.97万
  • 项目类别:
Interneurons as Early Drivers of Huntington´s Disease Progression
中间神经元是亨廷顿病进展的早期驱动因素
  • 批准号:
    10672973
  • 财政年份:
    2022
  • 资助金额:
    $ 61.97万
  • 项目类别:
Social Connectedness and Communication in Parents with Huntington''s Disease and their Offspring: Associations with Psychological and Disease Progression
患有亨廷顿病的父母及其后代的社会联系和沟通:与心理和疾病进展的关联
  • 批准号:
    10585925
  • 财政年份:
    2022
  • 资助金额:
    $ 61.97万
  • 项目类别:
Oligodendrocyte heterogeneity in Alzheimer' s disease
阿尔茨海默病中的少突胶质细胞异质性
  • 批准号:
    10180000
  • 财政年份:
    2021
  • 资助金额:
    $ 61.97万
  • 项目类别:
Serum proteome analysis of Alzheimer´s disease in a population-based longitudinal cohort study - the AGES Reykjavik study
基于人群的纵向队列研究中阿尔茨海默病的血清蛋白质组分析 - AGES 雷克雅未克研究
  • 批准号:
    10049426
  • 财政年份:
    2021
  • 资助金额:
    $ 61.97万
  • 项目类别:
Repurposing drugs for Alzheimer´s disease using a reverse translational approach
使用逆翻译方法重新利用治疗阿尔茨海默病的药物
  • 批准号:
    10295809
  • 财政年份:
    2021
  • 资助金额:
    $ 61.97万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了