Molecular Mechanisms Underlying Behavioral and Psychological Symptoms in Alzheimers Disease
阿尔茨海默病行为和心理症状的分子机制
基本信息
- 批准号:9788262
- 负责人:
- 金额:$ 70.47万
- 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:2018-09-30 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:APP-PS1AffectAffectiveAggressive behaviorAgitationAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmyloid depositionAnimal ModelAnimalsAnteriorAnxietyAppearanceAreaAutopsyBehaviorBehavior TherapyBehavioralBehavioral ModelBehavioral SymptomsBiochemicalBioinformaticsBrainCRISPR/Cas technologyCandidate Disease GeneCaregiversClinical assessmentsCollaborationsComputer softwareDataDatabasesDelusionsDementiaDevelopmentDiseaseDisease ProgressionDisinhibitionDistressElementsEtiologyExpression ProfilingFrequenciesFutureGene ExpressionGene Expression ProfileGenesGoalsHumanHyperactive behaviorImpaired cognitionIndividualInstitutionalizationInterventionInvestigationLeadLinkLiteratureMediatingMemory LossMemory impairmentMental DepressionMethodsModelingMolecularMusOnline Mendelian Inheritance In ManPathogenesisPathway AnalysisPathway interactionsPatientsPlayPrefrontal CortexPrevention strategyProteomicsPsychotic DisordersQuality of lifeResearchResearch PersonnelRiskRoleSeveritiesSignal PathwaySymptomsSyndromeTestingTg2576TherapeuticTherapeutic InterventionTime trendTissuesTransgenic MiceTransgenic OrganismsViralWestern BlottingWorkanalogbasecingulate cortexdisturbance in affectdysphoriagenetic manipulationhuman studyhuman subjecthuman tissueimmunocytochemistrymouse modelneuron lossneuronal circuitryneuropsychiatrynovelnovel therapeutic interventionparitypreventpsychological symptomsexsymptom clustertranscriptome sequencingtranslational pipelinetreatment strategy
项目摘要
Summary
Over 90% of Alzheimer's disease (AD) patients suffer from behavioral and psychological symptoms of
dementia (BPSD) including agitation, aggression, depression, apathy and psychosis. BPSD can present at
almost any stage of AD, and in some patients, these symptoms can even appear before dementia
develops. The severity of BPSD increases significantly with disease progression, and affects the quality of life
of both patients and their caregivers. In many patients, BPSD is the main reason for institutionalization.
However, the mechanisms underlying BPSD are not known, and there is no specific treatment strategy
available. Although BPSD presents differently in each patient, the presence of certain symptoms in a patient
make the co-occurrence of other symptoms more likely. In an ongoing collaboration with Rush Alzheimer's
Disease Center, we have developed a method for clustering the symptoms of BPSD into four domains
(affective, hyperactivity/disinhibition, psychosis and apathy). Based on these domains, we then conducted an
RNA-seq and found different gene expression profiles in AD patients with and without BPSD. This evidence
supports the notion that distinct molecular pathways may be involved in the appearance of BPSD. In this
proposal, we hypothesize that individual BPSD domains in patients with AD are due to definable perturbations
in molecular pathways and that these pathways can be analogized in AD mouse models, allowing for a causal
investigation of the relationship between specific pathway alterations and domain behaviors. We will test this
hypothesis through both human study and animal work. For the human study, 1) we will expand on our
behavioral analyses by increasing subjects for pre-mortem clinical assessments and defining BPSD trends
over time in AD patients. 2) Within each behavioral domain, we will employ RNA-seq to investigate gene
expression patterns in different brain sub-regions that are unique to each BPSD domain and the gene
expression pattern will be compared across normal, MCI and AD subjects. 3) Finally, we will identify which
pathways are most clearly associated with each of the BPSD domains using bioinformatics and biochemical
analyses. For the animal model work, 1) we will characterize how mouse behaviors analogous to human BPSD
symptoms evolve during AD-like neuropathgenesis progression 2) We will identify the most promising
molecular candidates for intervention from our RNA-seq findings using these AD/BPSD models. 3) Finally, we
will determine whether altering these pathways leads to changes in BPSD-like behavior using virally mediated
genetic manipulations (AAV9/CRISPR-Cas9). Overall, this project will establish a translational pipeline by
associating BPSD symptom domains with molecular alterations in human AD patients, and by demonstrating
that manipulations of these pathways can cause BPSD-like behaviors in transgenic mouse models of AD.
These data-driven approaches will lead to a better understanding of the molecular mechanisms that underlie
BPSD in AD and potentially identify novel targets for future therapeutic interventions.
总结
超过90%的阿尔茨海默病(AD)患者患有行为和心理症状,
痴呆(BPSD)包括激越、攻击、抑郁、冷漠和精神病。BPSD可以在
几乎任何阶段的AD,在一些患者中,这些症状甚至可以出现在痴呆症之前
发展起来的BPSD的严重程度随着疾病的进展而显著增加,并影响生活质量
病人和他们的护理人员的信息在许多患者中,BPSD是住院的主要原因。
然而,BPSD的潜在机制尚不清楚,也没有具体的治疗策略
available.虽然BPSD在每个患者中表现不同,但患者中某些症状的存在
使其他症状更有可能同时出现。在与拉什阿尔茨海默氏症正在进行的合作中,
疾病中心,我们已经开发了一种方法,用于将BPSD的症状聚类为四个领域
(情感、多动/去抑制、精神病和冷漠)。基于这些领域,我们进行了一项
RNA-seq和发现不同的基因表达谱在AD患者和没有BPSD。这一证据
支持不同的分子途径可能参与BPSD的出现的概念。在这
建议,我们假设,个别BPSD域在AD患者是由于可定义的扰动
在分子途径中,这些途径可以在AD小鼠模型中进行类比,
研究特定途径改变和域行为之间的关系。我们将测试这个
通过人类研究和动物实验的假设。对于人类研究,1)我们将扩大我们的
通过增加受试者进行尸检前临床评估和定义BPSD趋势进行行为分析
随着时间的推移,AD患者。2)在每个行为域中,我们将使用RNA-seq来研究基因
在不同的大脑亚区域的表达模式,是独特的每个BPSD结构域和基因
将在正常、MCI和AD受试者之间比较表达模式。3)最后,我们将确定
使用生物信息学和生物化学方法,
分析。对于动物模型工作,1)我们将描述小鼠行为如何类似于人类BPSD
症状在AD样神经病变进展过程中演变2)我们将确定最有希望的
使用这些AD/BPSD模型从我们的RNA-seq发现中筛选出干预的分子候选者。3)最后我们
将确定改变这些途径是否会导致BPSD样行为的变化,
基因操作(AAV 9/CRISPR-Cas9)。总的来说,该项目将通过以下方式建立翻译管道:
将BPSD症状域与人类AD患者的分子改变相关联,并通过证明
在AD转基因小鼠模型中,对这些通路的操纵可以引起BPSD样行为。
这些数据驱动的方法将有助于更好地理解
AD中的BPSD,并可能为未来的治疗干预确定新的靶点。
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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Hongxin Dong其他文献
Hongxin Dong的其他文献
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{{ truncateString('Hongxin Dong', 18)}}的其他基金
Epigenetic Regulation in Aging and Alzheimer's Disease
衰老和阿尔茨海默病的表观遗传调控
- 批准号:
10564831 - 财政年份:2022
- 资助金额:
$ 70.47万 - 项目类别:
Molecular Mechanisms Underlying Behavioral and Psychological Symptoms in Alzheimers Disease
阿尔茨海默病行为和心理症状的分子机制
- 批准号:
10452490 - 财政年份:2018
- 资助金额:
$ 70.47万 - 项目类别:
Molecular Mechanisms Underlying Behavioral and Psychological Symptoms in Alzheimers Disease
阿尔茨海默病行为和心理症状的分子机制
- 批准号:
10183128 - 财政年份:2018
- 资助金额:
$ 70.47万 - 项目类别:
Sex differences in central stress response and Alzheimer's disease neuropathology
中枢应激反应和阿尔茨海默病神经病理学的性别差异
- 批准号:
9924147 - 财政年份:2017
- 资助金额:
$ 70.47万 - 项目类别:
Age-Related Histone Modification Effect on Antipsychotic Action
年龄相关的组蛋白修饰对抗精神病作用的影响
- 批准号:
9281089 - 财政年份:2016
- 资助金额:
$ 70.47万 - 项目类别:
Age-Related Histone Modification Effect on Antipsychotic Action
年龄相关的组蛋白修饰对抗精神病作用的影响
- 批准号:
9077000 - 财政年份:2016
- 资助金额:
$ 70.47万 - 项目类别:
Aging and Antipsychotic Efficacy - Epigenetic Mechanisms
衰老和抗精神病药的功效——表观遗传机制
- 批准号:
8600189 - 财政年份:2012
- 资助金额:
$ 70.47万 - 项目类别:
Aging and Antipsychotic Efficacy - Epigenetic Mechanisms
衰老和抗精神病药的功效——表观遗传机制
- 批准号:
8445889 - 财政年份:2012
- 资助金额:
$ 70.47万 - 项目类别:
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