Mechanism of Gp1 mGluR-dependent translation and plasticity
Gp1 mGluR 依赖性翻译和可塑性机制
基本信息
- 批准号:10469161
- 负责人:
- 金额:$ 38.63万
- 依托单位:
- 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:2020-12-01 至 2025-10-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAlzheimer&aposs DiseaseAmyloid beta-ProteinAnimal ModelAwardCellular StressCellular Stress ResponseDataFMR1FemaleFutureGTPBP1 geneImpaired cognitionIn VitroKnowledgeMemory impairmentMolecularMusNerve DegenerationNeuronsParentsPathologyPeptide Elongation Factor 2PhosphorylationRegulationResearchRisk FactorsSex DifferencesSignal PathwaySignal TransductionSynaptic plasticityTranslationsUp-Regulationabeta accumulationbiological adaptation to stressimprovedin vivomalemouse modelneuronal circuitryneurotoxicnew therapeutic targetnovelsextool
项目摘要
PROJECT SUMMARY/ABSTRACT
Extensive studies have demonstrated that cellular stress and the subsequent stress response, such as
global translational suppression, are exaggerated in amyloid beta (Aβ)–associated Alzheimer’s disease and that
they facilitate neurodegeneration. Alleviating the stress response has been shown to improve neuronal and
circuit functions in animal models of Aβ pathology. However, our understanding of the molecular mechanisms
underlying Aβ-induced cellular stress response is limited. Furthermore, it is also unclear whether there is any
sex-specific regulation behind those mechanisms. To address these questions, we have gathered preliminary
data that reveal an Aβ-induced up-regulation of fragile X mental retardation protein (FMRP) and the FMRP-
dependent phosphorylation of eukaryotic translation elongation factor 2 (eEF2) and subsequent translational
suppression. Remarkably, our data also suggest that these mechanisms potentially occur only in female but not
in male mice in an Aβ-pathology mouse model. We therefore hypothesize that elevated FMRP induced by Aβ
contributes to exaggerated translational suppression and neurodegeneration, particularly in females. In Aim 1,
we propose to characterize, as well as reduce, Aβ-associated eEF2 phosphorylation to ameliorate translational
suppression in primary neurons in vitro. In Aim 2, we propose to study sex-specific regulation of FMRP and
translational suppression in Aβ pathology in vivo. We also propose to genetically inhibit FMRP to ameliorate Aβ-
induced neurodegeneration in mice in vivo. This supplemental research is within the scope of the Aim 3 of the
parent award in which the FMRP-dependent regulation of global translational suppression and synaptic plasticity
are being studied through phosphorylation signaling. Through the research of FMRP in Alzheimer’s disease, we
expect that our results will (1) elucidate a novel mechanism by which accumulation of Aβ leads to translational
suppression, (2) uncover a sex-specific regulation in translational suppression in Aβ pathology, and (3) suggest
novel therapeutic targets for ameliorating exaggerated cellular stress response and neurodegeneration in
Alzheimer’s disease. Building on existing tools and substantial knowledge of FMRP, our research has the
potential to quickly open new avenues for the future study of Alzheimer’s disease–associated cognitive decline
and memory impairment.
项目摘要/摘要
广泛的研究表明,细胞应激和随后的应激反应,如
全球翻译抑制在淀粉样β蛋白(Aβ)相关的阿尔茨海默病中被夸大,而且
它们会促进神经退化。缓解应激反应已被证明可以改善神经元和
电路在β病理动物模型中的作用。然而,我们对分子机制的理解
潜在的β诱导的细胞应激反应是有限的。此外,也不清楚是否有任何
这些机制背后有针对性别的监管。为了解决这些问题,我们收集了初步的
数据显示Aβ诱导的脆性X智力低下蛋白上调和脆性X智力低下蛋白-
真核细胞翻译延伸因子2(EEF2)的依赖磷酸化及其随后的翻译
压制。值得注意的是,我们的数据还表明,这些机制可能只发生在女性身上,而不是
在Aβ病理小鼠模型中的雄性小鼠中。因此,我们假设Aβ引起的FMRP升高
导致夸大的翻译抑制和神经变性,特别是在女性。在目标1中,
我们建议表征并减少β相关的eEF2磷酸化以改善翻译
体外培养的原代神经元抑制。在目标2中,我们建议研究FMRP和FMRP的性别特异性调控
体内β病理中的翻译抑制。我们还建议通过基因抑制FMRP来改善A-β-
在体内诱导小鼠神经变性。这项补充研究属于目标3的范围。
FMRP依赖的全球翻译抑制和突触可塑性调节的亲本奖
正在通过磷酸化信号转导进行研究。通过对阿尔茨海默病FMRP的研究,我们发现
预计我们的结果将(1)阐明一种新的机制,即Aβ的积累导致翻译
抑制,(2)揭示β病理中翻译抑制的性别特异性调节,以及(3)建议
新的治疗靶点,以改善夸大的细胞应激反应和神经变性
阿尔茨海默氏症。在现有工具和FMRP大量知识的基础上,我们的研究具有
有可能迅速为阿尔茨海默病相关认知障碍的未来研究开辟新的途径
以及记忆力减退。
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 }}
Nien-Pei Tsai其他文献
Nien-Pei Tsai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('Nien-Pei Tsai', 18)}}的其他基金
Transcriptional Mechanism underlying Neuronal Hyperexcitability in FXS
FXS 神经元过度兴奋的转录机制
- 批准号:
10746620 - 财政年份:2023
- 资助金额:
$ 38.63万 - 项目类别:
Mechanism of Gp1 mGluR-dependent translation and plasticity
Gp1 mGluR 依赖性翻译和可塑性机制
- 批准号:
10516050 - 财政年份:2020
- 资助金额:
$ 38.63万 - 项目类别:
Mechanism of Gp1 mGluR-dependent translation and plasticity
Gp1 mGluR 依赖性翻译和可塑性机制
- 批准号:
10094921 - 财政年份:2020
- 资助金额:
$ 38.63万 - 项目类别:
Study of PAK3 in epilepsy-associated defects in synaptic plasticity
PAK3在癫痫相关突触可塑性缺陷中的研究
- 批准号:
10046413 - 财政年份:2020
- 资助金额:
$ 38.63万 - 项目类别:
Exploring the role of p53 in synapse development and elimination
探索 p53 在突触发育和消除中的作用
- 批准号:
10055071 - 财政年份:2020
- 资助金额:
$ 38.63万 - 项目类别:
Mechanism of Gp1 mGluR-dependent translation and plasticity
Gp1 mGluR 依赖性翻译和可塑性机制
- 批准号:
10310451 - 财政年份:2020
- 资助金额:
$ 38.63万 - 项目类别:
AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability
AMPA 受体泛素化和病理性突触过度兴奋
- 批准号:
10327201 - 财政年份:2018
- 资助金额:
$ 38.63万 - 项目类别:
AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability
AMPA 受体泛素化和病理性突触过度兴奋
- 批准号:
10369620 - 财政年份:2018
- 资助金额:
$ 38.63万 - 项目类别:
AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability
AMPA 受体泛素化和病理性突触过度兴奋
- 批准号:
10596721 - 财政年份:2018
- 资助金额:
$ 38.63万 - 项目类别:
AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability
AMPA 受体泛素化和病理性突触过度兴奋
- 批准号:
10274787 - 财政年份:2018
- 资助金额:
$ 38.63万 - 项目类别: