The role of beta-secretase 1 (BACE1) in modulating excitatory synaptic and circuit function and behavior
β-分泌酶 1 (BACE1) 在调节兴奋性突触和回路功能和行为中的作用
基本信息
- 批准号:10607846
- 负责人:
- 金额:$ 4.32万
- 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:2023-02-22 至 2027-02-21
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAdverse effectsAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease therapeuticAlzheimer&aposs disease therapyAmyloid beta-ProteinBehaviorBehavioralBehavioral AssayBiochemicalBrainCause of DeathCellsCessation of lifeClinical SkillsClinical TrialsCognitionCognitive deficitsCommunicationDataDefectDementiaDevelopmentDevelopment PlansDiseaseDisease ProgressionElectrophysiology (science)EnzymesEquilibriumExcitatory SynapseFailureFutureGenerationsGeneticHealthHippocampusHumanImpaired cognitionImpairmentIon ChannelKnockout MiceKnowledgeLearningMembraneMembrane PotentialsMemoryMemory LossMemory impairmentMentorsMethodsMusMutant Strains MiceNeurodegenerative DisordersNeuronsPathologicPatientsPeptide HydrolasesPhasePhenotypePhysiciansPhysiologicalPhysiologyPlayPotassiumPropertyProsencephalonPublishingRegulationResearchRestRodentRodent ModelRoleScientistSeizuresSenile PlaquesSodiumSynapsesSynaptic TransmissionSynaptic plasticityTechnical ExpertiseTechniquesTestingTherapeuticTrainingTransgenic Organismsabeta accumulationabeta oligomerage related neurodegenerationbehavioral studybeta-site APP cleaving enzyme 1careercell typecognitive functiondesigner receptors exclusively activated by designer drugsdoctoral studentdrug developmentepileptiformexcitatory neuronexperienceextracellulargenetic approachgenetic manipulationhippocampal pyramidal neuronin vivoinhibitorinsightmutantneuronal circuitryneuronal excitabilityneurophysiologyneurotoxicitynovelpatch clamppresynapticpreventskillssynaptic functiontherapeutic targetvoltage
项目摘要
PROJECT SUMMARY
Alzheimer’s Disease (AD), the most common cause of dementia, is a debilitating disease that leads to
progressive memory loss, cognitive impairment, and ultimately death. Pathological hallmarks of AD include
extracellular amyloid beta (Aβ) plaques. β-secretase-1 (β-site APP cleaving enzyme 1, BACE1) is the rate-
limiting enzyme of toxic Aβ generation. Transgenic BACE1 KO mouse models of AD led to suppression of AD
pathology, which suggests that inhibiting BACE1 may be a rational strategy for AD treatment. However, human
clinical trials have shown that BACE1 inhibitors are inefficacious, even worsening cognitive function, among AD
patients. This benchtop-to-bedside translational failure is due to our incomplete understanding of BACE1’s
physiological function. In particular, the mechanisms underlying neuronal and synaptic impairments in BACE1
deficiency or inhibition is poorly understood. In this proposal, we will address this knowledge gap by testing the
hypothesis that BACE1 modulates intrinsic and synaptic neurophysiological properties in a cell-type- and circuit-
specific manner in the hippocampus, a major substrate of memory storage derailed by AD. My preliminary data
of whole-cell patch clamp of hippocampal pyramidal neurons (PNs) show that selective BACE1 deletion in
excitatory neurons leads to neuronal hyperexcitability, suggesting that BACE1 deletion disrupts intrinsic neuronal
function in a cell-autonomous manner. Given my preliminary findings, I hypothesize that BACE1 modulates
excitability and synaptic transmission in hippocampal PNs by the regulation of ion channels – the identities of
which have yet to be fully elucidated. In Aim 1, I will comprehensively determine the ionic basis underlying the
hyperexcitability phenotype in my Excitatory-BACE1-KO mice (mice in which BACE1 is selectively deleted in
excitatory PNs), and characterize the synaptic transmission and plasticity deficits in Excitatory-BACE1-KO,
through patch clamp electrophysiology methods. In Aim 2, I will delineate behavioral deficits Excitatory-BACE1-
KO neurons, and rescue hypothesized cognitive deficits in mutant mice by normalizing PN hyperexcitability
through a chemogenetic approach. The findings from this study will provide insight into neuronal and synaptic
physiology, mechanisms of learning/memory and behavior, and future AD therapeutic strategies. Importantly,
completion of this project will help me master current concepts and state-of-the-art techniques in patch clamp
electrophysiology, behavior studies, and in vivo genetic perturbation and increase my scientific communication
skills through extensive opportunities to present and publish my studies. As an MD/PhD student at UConn Health,
I will have access to mentors and experts that will not only directly facilitate my mastery of the necessary technical
skills, but I will also have opportunities to continue honing my clinical skills and gain specialized experience
during and after my research phase. Fulfilling my training and development plan will be a crucial step toward my
future career as a physician-scientist studying the mechanisms underlying neurodegenerative disease in
patients.
项目总结
阿尔茨海默病(AD)是导致痴呆症的最常见原因,是一种使人衰弱的疾病,会导致
进行性记忆丧失,认知障碍,最终死亡。阿尔茨海默病的病理特征包括
细胞外淀粉样β蛋白(Aβ)斑块。β-分泌酶-1(β-Site APP裂解酶1,BACE1)是指-
产生毒性Aβ的限制酶。转基因BACE1KO小鼠AD模型对AD的抑制作用
这表明抑制BACE1可能是治疗AD的一种合理策略。然而,人类
临床试验表明,在阿尔茨海默病患者中,BACE1抑制剂无效,甚至恶化认知功能
病人。这种从桌上到床边的翻译失败是因为我们对北京一号线的S了解不够全面
生理功能。特别是,BACE1中神经元和突触损伤的潜在机制
对缺乏或抑制知之甚少。在本提案中,我们将通过测试
假设BACE1调节细胞类型和回路中的固有和突触神经生理特性-
特定的方式在海马体,一个主要的底物的记忆存储脱轨AD。我的初步数据
海马锥体神经元(PNS)全细胞膜片钳的研究表明,BACE1选择性缺失在
兴奋性神经元导致神经元超兴奋性,提示BACE1缺失扰乱了固有神经元
以细胞自主的方式运作。根据我的初步发现,我假设BACE1调节
离子通道调节的海马三叉神经节兴奋性和突触传递
这些都还没有完全阐明。在目标1中,我将全面确定
我的兴奋性-BACE1-KO小鼠(其中BACE1选择性缺失的小鼠)的超兴奋性表型
兴奋性PNS),并对兴奋性BACE1-KO的突触传递和可塑性缺陷进行了表征,
通过膜片钳电生理学方法。在目标2中,我将描述行为缺陷兴奋性-BACE1-
KO神经元,并通过正常化PN超兴奋性来挽救突变小鼠假想的认知缺陷
通过化学遗传学的方法。这项研究的发现将提供对神经元和突触的洞察
生理,学习/记忆和行为的机制,以及未来的AD治疗策略。重要的是
这个项目的完成将帮助我掌握膜片钳的当前概念和最先进的技术
电生理学、行为研究和体内遗传干扰,增加了我的科学交流
通过广泛的机会展示和发表我的研究成果。作为康涅狄格州大学健康学院的一名医学博士/博士研究生,
我将有机会接触到导师和专家,他们不仅会直接帮助我掌握必要的技术
技能,但我也将有机会继续磨练我的临床技能并获得专业经验
在我的研究阶段期间和之后。完成我的培训和发展计划将是迈向我
未来的职业生涯是一名内科科学家,研究神经退行性疾病的潜在机制
病人。
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 }}
ANNIE Y YAO其他文献
ANNIE Y YAO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 }}
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 4.32万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 4.32万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 4.32万 - 项目类别:
Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 4.32万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 4.32万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 4.32万 - 项目类别:
Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
- 批准号:
2230829 - 财政年份:2023
- 资助金额:
$ 4.32万 - 项目类别:
Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 4.32万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 4.32万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 4.32万 - 项目类别:
Grant-in-Aid for Scientific Research (C)