Exploring the role of GADD45A in Alzheimer's disease
Exploring the role of GADD45A in Alzheimer's disease
批准号:
10373344
负责人:
Andrew P Escayg
金额:
$41.61万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-02-01 至 2024-01-31
关键词:
3xTg-AD mouseATAC-seqAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease patientAmericanBehaviorBinding ProteinsBiologicalBrainCellsChromatinClinicalCognitionCognitiveCognitive deficitsDNADNA MethylationDataData SetDementiaDioxygenasesEconomic BurdenEpigenetic ProcessEpilepsyExhibitsFamilyGADD45A geneGene ExpressionGenesGenetic TranscriptionGlutamate ReceptorGoalsHealthcare SystemsHippocampus (Brain)Impaired cognitionImpairmentIntensive CareInterventionKnockout MiceLearningLinkLong-Term PotentiationMediatingMemoryMemory LossMessenger RNAModificationMolecularMusMutant Strains MiceN-MethylaspartateNerve DegenerationNeurodegenerative DisordersNeuronsOxidesPathogenesisPathologicPathway interactionsPatientsPharmacologyPhenotypePlayProteinsRNA BindingRegulationReversal LearningRiskRoleSynapsesSynaptic plasticityTestingTherapeuticTranscriptTranslatingUp-RegulationWild Type Mousebaseclinically relevantcomorbidityeffective therapyefficacious treatmentepigenetic regulationexcitatory neuronfamily burdengene repressiongenome-widegenomic locusimprovedlong term memorymemory consolidationmouse modelmutantnervous system disorderneurodevelopmentoverexpressionpreventrecruitsynaptic functiontranscriptome sequencing
中文摘要
项目总结
阿尔茨海默病(AD)是一种严重的痴呆症,影响着500多万美国人,使其成为
最常见的神经退行性疾病。AD患者表现出严重的渐进性记忆
目前的药物干预无法预防这种损失,并有更高的发生风险
共病的神经系统疾病,如癫痫。缺乏有效的治疗和重症监护
晚期AD患者所需费用也给家庭和美国人带来了巨大的经济负担
医疗保健系统:估计每年约为2000亿美元。最近的研究表明,
表观遗传修饰和AD。一种特别相关的表观遗传学修饰是5-羟甲基胞嘧啶
(5hmC),它在神经元中高度丰富,并在神经发育期间受到动态调节。改建
在AD患者的大脑和小鼠AD模型中观察到了5hmC,增加了这种可能性
DNA 5hmC的异常可能参与了AD的发病。GADD45A介导5hmC的建立
并具有RNA结合活性。有趣的是,Gadd45a/空小鼠表现出减少
海马长时程增强(LTP)和长时记忆和反转学习受损,而
Gadd45a在野生型小鼠锥体兴奋性神经元中的过表达增强LTP和记忆
整合。此外,我们初步数据和公开提供的RNA-SEQ数据集表明,GADD45A
在AD患者分离的神经元中表达下调。Gadd45a表达和5hmC水平也降低
在AD的几个小鼠模型中(包括本提案中使用的3xTg AD模型)。基于这些
观察到,我们假设GADD45A在神经元功能和认知中发挥重要作用
通过表观遗传调控5hmC水平和随后的基因表达调控
神经元。我们将在目标1中通过比较Gadd45a-/-之间的5hmC水平和分布来检验这一假设
零突变体和WT窝产仔。我们还将对这些小鼠进行RNA-seq和atac-seq的功能测试
将观察到的5hmC变化与基因表达和染色质可及性的特定变化联系起来。vt.给出
Gadd45a的过度表达增强了LTP和记忆巩固,我们假设
GADD45A的上调在AD中将具有治疗作用。因此,在目标2中,我们将研究
Gadd45a在3xTg AD小鼠模型中的过表达可改善突触活性缺陷,改善
学习和记忆,并减少自发癫痫样放电。这些表型是被选中的
因为它们代表了阿尔茨海默病的重要病理特征,并且自认知以来在机制上相关
阿尔茨海默病大脑的衰退被认为是由于神经元的过度兴奋而加速的。
英文摘要
PROJECT SUMMARY
Alzheimer’s disease (AD) is a severe form of dementia that affects over 5 million Americans, making it one of
the most common neurodegenerative disorders. Patients with AD exhibit a severe form of progressive memory
loss that cannot be prevented with current pharmacological interventions, and are at increased risk of developing
comorbid neurological disorders such as epilepsy. The lack of efficacious treatments and the intensive care
required for late-stage AD patients also places a significant economic burden on families and the American
healthcare system: an estimated ~$200 billion annually. Recent studies have demonstrated a link between
epigenetic modifications and AD. One epigenetic modification of particular relevance is 5-hydroxymethylcytosine
(5hmC) which is highly enriched in neurons and is dynamically regulated during neurodevelopment. Alterations
in 5hmC have been observed in the brains of patients with AD and in mouse AD models, raising the possibility
that aberrant DNA 5hmC might contribute to AD pathogenesis. GADD45A mediates the establishment of 5hmC
in cells and also possesses RNA binding activity. Interestingly, Gadd45a-/- null mice exhibit decreased
hippocampal long-term potentiation (LTP) and impaired long-term memory and reversal learning, whereas
overexpression of Gadd45a in pyramidal excitatory neurons of wild-type mice enhances LTP and memory
consolidation. In addition, our preliminary data and publicly available RNA-seq data sets indicate that GADD45A
is downregulated in neurons isolated from AD patients. Gadd45a expression and 5hmC levels are also reduced
in several mouse models of AD (including the 3xTG AD model to be used in this proposal). Based on these
observations, we hypothesize that GADD45A plays an important role in neuronal function and cognition
through epigenetic regulation of 5hmC levels and subsequent modulation of gene expression in
neurons. We will test this hypothesis in Aim 1 by comparing 5hmC levels and distribution between Gadd45a-/-
null mutants and WT littermates. We will also perform RNA-seq and ATAC-seq on these mice to functionally
relate observed changes in 5hmC with specific alterations in gene expression and chromatin accessibility. Given
that overexpression of Gadd45a enhances LTP and memory consolidation, we hypothesize that
upregulation of GADD45A will be therapeutic in AD. Therefore, in Aim 2, we will examine whether
overexpression of Gadd45a in the 3xTG mouse model of AD can ameliorate deficits in synaptic activity, improve
learning and memory, and reduce spontaneous epileptiform discharges. These phenotypes were selected
because they represent important pathological features of AD and are mechanistically related since cognitive
decline in the AD brain is believed to be accelerated by neuronal hyperexcitability.
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