Estrogenic regulation of the hippocampal ubiquitin-proteasome system and its role in memory and structural plastcity
海马泛素-蛋白酶体系统的雌激素调节及其在记忆和结构可塑性中的作用
基本信息
- 批准号:10735271
- 负责人:
- 金额:$ 51.61万
- 依托单位:
- 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:2023-07-15 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:26S proteasomeActinsAddressAdultAlzheimer&aposs DiseaseAnxiety DisordersAutomobile DrivingBrainCharacteristicsComplexDataDendritic SpinesDevelopmentDorsalEstradiolEstrogen ReceptorsEtiologyFemaleFunctional disorderGenerationsGlutamate ReceptorGoalsGonadal Steroid HormonesHippocampusIon ChannelKnowledgeMass Spectrum AnalysisMeasuresMediatingMemoryMemory impairmentMental DepressionMental disordersMissionMolecularMusNational Institute of Neurological Disorders and StrokeNervous SystemNeuronsNuclearOutcomePathway AnalysisPatientsPersonsPharmacologyPlayPolymersPolyubiquitinationProteasome InhibitionProtein BiosynthesisProteinsProteomicsPublic HealthPublishingRegulationReport (document)ResearchRodentRoleSex DifferencesSignal TransductionSliceSynapsesSynaptic plasticitySystemTestingTissuesUbiquitinVertebral columnWomanWorkbehavioral outcomecalmodulin-dependent protein kinase IIdensityeffective therapyestrogenichormone regulationin vivoinnovationinsightmalememory consolidationmenmulticatalytic endopeptidase complexnervous system disorderneuromechanismneuropsychiatric disorderneuropsychiatrynovelnovel therapeuticspharmacologicpolymerizationprotein degradationreceptorsexubiquitin mediated proteasome degradation
项目摘要
Project Summary
Memory impairment is a defining characteristic of many neuropsychiatric disorders, however, an understanding
of the complex neural mechanisms regulating hippocampal memory formation remains elusive. The sex steroid
17β-estradiol (E2) is a powerful modulator of hippocampal plasticity and memory in both males and females,
however the neural mechanisms through which this occurs are poorly understood. Therefore, the long-term goal
of our research is to pinpoint the neural mechanisms through which E2 regulates hippocampal memory
consolidation in males and females. The overall objectives of this application are to determine the mechanisms
through which E2 regulates activity of the ubiquitin proteasome system (UPS) and the extent to which
proteasomal protein degradation contributes to estrogenic regulation of memory consolidation and hippocampal
dendritic spine density in both sexes. Although UPS-mediated protein degradation in the hippocampus is
essential for synaptic remodeling and memory consolidation, the role that UPS activity plays in mediating E2’s
modulatory effects on memory formation and spine remodeling in either sex remains completely unexplored. Our
central hypothesis is that UPS-mediated protein degradation in the DH is triggered by E2 acting at estrogen and
glutamate receptors and is a principal mechanism through which E2 promotes memory consolidation and CA1
spine density. This hypothesis is based on previous work suggesting overlapping mechanisms through which E2
and UPS activity contribute to hippocampal plasticity and memory. Our central hypothesis will be evaluated in
the following three specific aims: 1) determine the cellular mechanisms through which E2 activates hippocampal
UPS activity, 2) identify protein targets of E2-induced UPS activation across subcellular compartments, 3)
establish a key role for proteasome activity in E2-induced facilitation of memory consolidation and CA1 spine
density. Regionally- and temporally- specific pharmacological manipulations will be used to establish receptor
mechanisms underlying E2-UPS interactions in the dorsal hippocampus, as well as the structural and behavioral
outcomes of these interactions. Cutting edge ubiquitin-specific mass spectrometry-based proteomics will also be
used to identify novel proteins targeted by E2 for degradation. This work is innovative in that it represents a
fundamental shift from a conventional focus on protein synthesis as a primary contributor to estrogenic memory
modulation to a novel consideration of protein degradation as an equal and opposite counterpart necessary for
estrogenic regulation of hippocampal plasticity and memory. This contribution is significant because it will provide
essential foundational knowledge about the mechanisms through which E2 regulates memory consolidation in
both sexes, which could lead to the development of novel sex-specific treatments to address the memory
dysfunction observed in numerous mental disorders.
项目概要
记忆障碍是许多神经精神疾病的一个决定性特征,然而,理解
调节海马记忆形成的复杂神经机制仍然难以捉摸。性类固醇
17β-雌二醇 (E2) 是男性和女性海马可塑性和记忆力的强大调节剂,
然而,人们对发生这种情况的神经机制知之甚少。因此,长期目标
我们研究的目的是查明 E2 调节海马记忆的神经机制
男性和女性的巩固。该应用程序的总体目标是确定机制
E2 通过其调节泛素蛋白酶体系统 (UPS) 的活性以及调节的程度
蛋白酶体蛋白降解有助于记忆巩固和海马的雌激素调节
两性的树突棘密度。尽管 UPS 介导的海马蛋白降解是
UPS 活动在调节 E2 的过程中发挥的作用对于突触重塑和记忆巩固至关重要
对两性记忆形成和脊柱重塑的调节作用仍然完全未被探索。我们的
中心假设是 DH 中 UPS 介导的蛋白质降解是由 E2 作用于雌激素和
谷氨酸受体,是 E2 促进记忆巩固和 CA1 的主要机制
脊柱密度。该假设基于先前的工作,表明 E2 通过重叠机制
UPS 活动有助于海马体的可塑性和记忆力。我们的中心假设将在
以下三个具体目标:1)确定E2激活海马的细胞机制
UPS 活性,2) 识别 E2 诱导的跨亚细胞区室 UPS 激活的蛋白质靶标,3)
确定蛋白酶体活性在 E2 诱导的记忆巩固和 CA1 脊柱促进过程中的关键作用
密度。将使用区域和时间特定的药理学操作来建立受体
背侧海马 E2-UPS 相互作用的潜在机制,以及结构和行为
这些相互作用的结果。基于泛素特异性质谱的尖端蛋白质组学也将
用于识别 E2 降解的新蛋白质。这项工作的创新之处在于它代表了
从传统的关注蛋白质合成作为雌激素记忆的主要贡献者的根本转变
调节蛋白质降解作为同等和相反的对应物的新考虑
海马可塑性和记忆的雌激素调节。这一贡献意义重大,因为它将提供
有关 E2 调节记忆巩固机制的重要基础知识
两种性别,这可能会导致开发新的针对性别的治疗方法来解决记忆问题
在许多精神障碍中观察到功能障碍。
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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Karyn M Frick其他文献
Karyn M Frick的其他文献
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{{ truncateString('Karyn M Frick', 18)}}的其他基金
UW-Milwaukee Promoting Equity, Diversity, and Academic Success Through Aging Research Program (UWM STAR)
威斯康星大学密尔沃基分校通过老龄化研究项目促进公平、多样性和学业成功 (UWM STAR)
- 批准号:
10626597 - 财政年份:2023
- 资助金额:
$ 51.61万 - 项目类别:
Mechanisms underlying memory regulation by 17beta-estradiol, canonical Wnt signaling, and BDNF in male and female mice
雄性和雌性小鼠中 17β-雌二醇、经典 Wnt 信号传导和 BDNF 记忆调节的机制
- 批准号:
9757819 - 财政年份:2016
- 资助金额:
$ 51.61万 - 项目类别:
Hormone and enrichment effects on memory in aging mice
激素和浓缩对衰老小鼠记忆力的影响
- 批准号:
7255624 - 财政年份:2005
- 资助金额:
$ 51.61万 - 项目类别:
Hormone and enrichment effects on memory in aging mice
激素和浓缩对衰老小鼠记忆力的影响
- 批准号:
6979946 - 财政年份:2005
- 资助金额:
$ 51.61万 - 项目类别:
Hormone and enrichment effects on memory in aging mice
激素和浓缩对衰老小鼠记忆力的影响
- 批准号:
7646244 - 财政年份:2005
- 资助金额:
$ 51.61万 - 项目类别:
Hormone and enrichment effects on memory in aging mice
激素和浓缩对衰老小鼠记忆力的影响
- 批准号:
7122783 - 财政年份:2005
- 资助金额:
$ 51.61万 - 项目类别:
Hormone and enrichment effects on memory in aging mice
激素和浓缩对衰老小鼠记忆力的影响
- 批准号:
7474011 - 财政年份:2005
- 资助金额:
$ 51.61万 - 项目类别:
Estrogenic-cholinergic interactions in memory modulation
记忆调节中的雌激素-胆碱能相互作用
- 批准号:
6574123 - 财政年份:2002
- 资助金额:
$ 51.61万 - 项目类别:
Estrogenic-cholinergic interactions in memory modulation
记忆调节中的雌激素-胆碱能相互作用
- 批准号:
6686809 - 财政年份:2002
- 资助金额:
$ 51.61万 - 项目类别:
HORMONE EFFECTS ON MEMORY AND NEUROBIOLOGY IN AGING MICE
激素对衰老小鼠记忆和神经生物学的影响
- 批准号:
2865456 - 财政年份:1999
- 资助金额:
$ 51.61万 - 项目类别:
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