Calcium dysregulation and vulnerability of entorhinal cortex neurons in Alzheimer's disease
阿尔茨海默病中的钙失调和内嗅皮层神经元的脆弱性
基本信息
- 批准号:10733805
- 负责人:
- 金额:$ 73.08万
- 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:2023-08-01 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAge MonthsAlzheimer&aposs DiseaseAlzheimer&aposs disease modelApplications GrantsBehavioralBiochemicalCalcineurinCalcineurin inhibitorCalciumCalcium SignalingCell DeathCognitiveCommunicationDataDefectDementiaDependovirusDetectionDevelopmentDiseaseDominant-Negative MutationDoxycyclineElderlyElectrophysiology (science)EvaluationEvolutionFK506Functional disorderHealthHippocampusHumanImageImpaired cognitionIn VitroIncidenceLabelLaboratoriesLateralLearningLightMediatingMemory impairmentMicroscopyMolecularMusNeurodegenerative DisordersNeuronsOutcomePathogenesisPathologyPatientsPeptidylprolyl IsomerasePeripheralPharmaceutical PreparationsPlayProteinsPublic HealthPublishingResearch PersonnelResistanceRoleScheduleSignal TransductionSliceStructureSynapsesTalentsTechniquesTestingTherapeutic AgentsTherapeutic InterventionTissuesTransplant Recipientsbehavioral studycalcineurin phosphatasecognitive functionconditioned feardentate gyrusdosageeffective therapyentorhinal cortexexcitatory neuronexperienceexperimental studyin vivoinnovationloss of functionmicroscopic imagingmouse modelmutantnetwork dysfunctionneuron lossneuropathologyneuroprotectionnovelobject recognitionoverexpressionpromoterprospectivepublic health relevancerestorationstructural imagingtherapeutically effectivetransplantation therapyvector
项目摘要
ABSTRACT
The broad, long-term objective of this multi-PI grant application is to understand the role of calcium (Ca2+)
dysregulation as the mechanistic driver for synaptic loss between the lateral entorhinal cortex (LEC) and
hippocampus (HPC) in evolving Alzheimer’s disease (AD). While dysfunction of the LEC-HPC circuit has been
implicated, the cause of the early, selective vulnerability of LEC neurons and projections remain unknown. We
will test the hypothesis that dysregulation of neuronal Ca2+ signaling plays a key role in LEC-HPC circuit
dysfunction in early AD. Specifically, in experiments with the APPKI mouse model of AD, we will investigate
if normalization of the activity of two key proteins, the Ca2+-dependent phosphatase calcineurin (CaN) or
the prolyl isomerase, Pin1 rescues defects in LEC–HPC communication, function and stability in early
AD. Pin1 is a key target of CaN-mediated inhibition in neurons, directly leading to synaptic and neuronal loss. In
experiments with APPKI mice, we will also determine if dominant negative Pin1 accelerates defects in
LEC–HPC communication irrespective of CaN normalization in APPKI mice. We will use a combination of
molecular, biochemical, imaging, electrophysiological, behavioral and neuropathological techniques to address
these specific aims. The proposed studies, if successful, will provide a mechanistic understanding of early AD
evolution as well as a rationale for the use of CaN inhibitors such as FK506 or voclosporin to treat early AD.
摘要
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
SpineTool is an open-source software for analysis of morphology of dendritic spines.
- DOI:10.1038/s41598-023-37406-4
- 发表时间:2023-06-29
- 期刊:
- 影响因子:4.6
- 作者:Ekaterina, Pchitskaya;Peter, Vasiliev;Smirnova, Daria;Vyacheslav, Chukanov;Ilya, Bezprozvanny
- 通讯作者:Ilya, Bezprozvanny
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Ilya B Bezprozvanny其他文献
Ilya B Bezprozvanny的其他文献
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{{ truncateString('Ilya B Bezprozvanny', 18)}}的其他基金
Sigma 1 receptor as therapeutic target for Alzheimers disease treatment
Sigma 1 受体作为阿尔茨海默病治疗靶点
- 批准号:
10901028 - 财政年份:2023
- 资助金额:
$ 73.08万 - 项目类别:
Calcium dysregulation and vulnerability of entorhinal cortex neurons in Alzheimer's disease
阿尔茨海默病中的钙失调和内嗅皮层神经元的脆弱性
- 批准号:
10459711 - 财政年份:2021
- 资助金额:
$ 73.08万 - 项目类别:
Calcium signaling and synaptic maintenance in Alzheimers disease
阿尔茨海默病中的钙信号传导和突触维持
- 批准号:
9285585 - 财政年份:2017
- 资助金额:
$ 73.08万 - 项目类别:
Development of SK channel modulators as therapeutic agents for ataxia
开发 SK 通道调节剂作为共济失调治疗剂
- 批准号:
10311149 - 财政年份:2017
- 资助金额:
$ 73.08万 - 项目类别:
Calcium channels as novel therapeutic targets for Huntingtons Disease
钙通道作为亨廷顿病的新治疗靶点
- 批准号:
8704830 - 财政年份:2012
- 资助金额:
$ 73.08万 - 项目类别:
Calcium channels as novel therapeutic targets for Huntingtons Disease
钙通道作为亨廷顿病的新治疗靶点
- 批准号:
8263938 - 财政年份:2012
- 资助金额:
$ 73.08万 - 项目类别:
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