AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability
AMPA 受体泛素化和病理性突触过度兴奋
基本信息
- 批准号:10274787
- 负责人:
- 金额:$ 35.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:AMPA ReceptorsAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAlzheimer&aposs disease therapyAmyloid beta-ProteinAmyloid beta-Protein PrecursorAntiepileptic AgentsAreaAwardCaregiversClinicalDevelopmentEpilepsyGenesGenetsIn VitroKnowledgeMutationNeuronsOnset of illnessParentsPathologicPatientsPredispositionProteinsReportingResearchRiskRisk FactorsRoleSeizuresSynapsesTemporal Lobe EpilepsyTestingUbiquitinationbasecomorbidityearly onsetin vivoin vivo Modelmouse modelnerve stem cellneuronal excitabilitynew therapeutic targetnovelparent grantpresenilintherapeutic targetubiquitin-protein ligase
项目摘要
PROJECT SUMMARY/ABSTRACT
A substantial amount of clinical reports have confirmed that patients with Alzheimer’s disease are at
increased risk for developing seizures and/or epilepsy. The seizures in Alzheimer’s disease have been shown
to occur more often with the early-onset disease, particularly when there is a familial presenilin I (PS1) mutation
or abnormal expression of amyloid precursor protein (APP). This non-psychiatric comorbidity causes significant
burden to the patients as well as the caregivers. However, our knowledge in this area is very limited.
Understanding the mechanisms underlying Alzheimer’s disease-associated seizures may reveal novel risk
factors and provide the opportunity to develop specific anti-epileptic therapies for Alzheimer’s disease patients.
Through support from the parent award, our recent studies have confirmed the role of ubiquitin E3 ligase neural
precursor cell expressed developmentally downregulated gene 4-like (Nedd4-2) in reducing neuronal excitability
in vitro and seizure susceptibility in vivo (Zhu et al., PLOS Genet, 2017; Lee et al., Hum Mol Genet, 2018; Zhu
et al., J Neurochem, 2019). Based on a preliminary observation showing a reduction of Nedd4-2 in an
Alzheimer’s disease mouse model and in primary neuronal cultures treated with amyloid beta (Aβ), the
pathological cleavage product of APP, we hypothesize that the reduction of Nedd4-2 induced by Aβ contributes
to elevated neuronal excitability and seizure susceptibility in Alzheimer’s disease. In the supplemental research
Aim 1, we propose to determine the mechanism by which Aβ induces a reduction of Nedd4-2. In the
supplemental research Aim 2, we propose to test whether re-expressing Nedd4-2 is sufficient to reverse
neuronal hyperexcitability in the presence of Aβ in vitro and ex vivo. In the supplemental research Aim 3, we
propose to determine whether re-expressing Nedd4-2 is sufficient to reduce seizure susceptibility in an
Alzheimer’s disease mouse model in vivo. The supplemental research being proposed is within the scope of
the Aim 3 of the parent award in which the function of Nedd4-2 in reducing seizure susceptibility in temporal
lobe epilepsy (TLE) is being studied. Through the research on Nedd4-2 in Alzheimer’s disease, we expect our
results to: (1) elucidate the mechanism underlying dysregulation of Nedd4-2 in Alzheimer’s disease; (2) uncover
an alteration of a key molecule (Nedd4-2) that leads to elevated seizure susceptibility in Alzheimer’s disease;
and (3) suggest novel therapeutic targets and potential therapies for Alzheimer’s disease-associated seizures
and epilepsy.
项目总结/摘要
大量的临床报告已经证实,阿尔茨海默病患者在
发生癫痫和/或癫痫的风险增加。阿尔茨海默氏症的癫痫已经被证明
早发性疾病更常发生,特别是当存在家族性早老素I(PS1)突变时
或淀粉样前体蛋白(APP)表达异常。这种非精神病合并症会导致严重的
给病人和护理人员带来负担。然而,我们在这方面的知识非常有限。
了解阿尔茨海默病相关癫痫发作的潜在机制可能揭示新的风险
这些因素,并提供了机会,开发特定的抗癫痫治疗阿尔茨海默病患者。
通过来自父母奖的支持,我们最近的研究已经证实了泛素E3连接酶神经
前体细胞表达发育下调基因4-like(Nedd 4 -2)降低神经元兴奋性
体外和体内癫痫易感性(Zhu等人,PLOS Genet,2017; Lee等人,分子遗传学,2018;朱
例如,J Neurochem,2019)。根据初步观察,Nedd 4 -2在一个
在阿尔茨海默病小鼠模型和用淀粉样蛋白β(Aβ)处理的原代神经元培养物中,
APP的病理性裂解产物,我们假设Aβ诱导的Nedd 4 -2的减少有助于
阿尔茨海默病中神经元兴奋性和癫痫易感性的升高。在补充研究中,
目的1,我们提出确定Aβ诱导Nedd 4 -2减少的机制。在
补充研究目的2,我们建议测试重新表达Nedd 4 -2是否足以逆转
在体外和离体Aβ存在下的神经元过度兴奋性。在补充研究目标3中,我们
我们建议确定重新表达Nedd 4 -2是否足以降低癫痫发作的易感性。
阿尔茨海默病小鼠体内模型。拟议的补充研究属于
父母奖励的目标3,其中Nedd 4 -2在降低癫痫发作易感性中的作用,
叶癫痫(TLE)正在研究中。通过对Nedd 4 -2在阿尔茨海默病中的研究,我们期待我们的
结果:(1)阐明阿尔茨海默病中Nedd 4 -2失调的潜在机制;(2)揭示
导致阿尔茨海默病中癫痫易感性升高的关键分子(Nedd 4 -2)的改变;
以及(3)为阿尔茨海默病相关癫痫发作提供新的治疗靶点和潜在疗法
和癫痫。
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)
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Nien-Pei Tsai其他文献
Nien-Pei Tsai的其他文献
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{{ 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:
$ 35.87万 - 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:
$ 35.87万 - 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:
$ 35.87万 - 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:
$ 35.87万 - 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:
10469161 - 财政年份:2020
- 资助金额:
$ 35.87万 - 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:
$ 35.87万 - 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:
$ 35.87万 - 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:
$ 35.87万 - 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:
$ 35.87万 - 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:
$ 35.87万 - 项目类别: