The Role of DNA Demethylation by Gadd45b in Memory and Synaptic Plasticity

Gadd45b DNA 去甲基化在记忆和突触可塑性中的作用

• 批准号: 8464577
• 负责人: Faraz Ali Sultan
• 金额: $ 1.78万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464577
• 关键词: Ablation; Acute; Address; Affect; Age; Age-associated memory impairment; Animals; Behavior; Behavioral; Binding; Brain; Brain region; Cells; Chromatin; Chromatin Structure; Cognition; Cognition Disorders; Complex; Core Protein; CpG dinucleotide; Cytosine; DNA; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; DNA methyltransferase inhibition; Data; Disease; Drug Targeting; Engineering; Epigenetic Process; Event; Exhibits; Family; Functional disorder; GADD45; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic; Genetic Transcription; Genotype; Half-Life; Healthcare; Hippocampus (Brain); Histone Acetylation; Histone Deacetylase; Histone deacetylase inhibition; Histones; Immediate-Early Genes; In Vitro; Investigation; Learning; Light; Link; Long-Term Potentiation; Measures; Mediating; Mediator of activation protein; Memory; Memory Disorders; Methylation; Modification; Molecular; Mus; Mutant Strains Mice; Neurodegenerative Disorders; Neurons; Pattern; Phenotype; Physiological; Play; Population; Prevalence; Process; Protein Biosynthesis; Protein Isoforms; Proteins; Protocols documentation; Rattus; Reaction; Regulation; Reporting; Research; Research Design; Research Proposals; Role; Signal Transduction; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic; Training; Transcriptional Regulation; United States; base; care burden; chromatin modification; classical conditioning; cognitive function; conditioned fear; demethylation; design; effective therapy; experience; histone modification; in vivo; insight; long term memory; memory process; memory retrieval; mutant; novel; promoter; protein function; response

Project Summary Disorders of memory remain a major health care burden in the United States. As the population ages, the prevalence of aging-associated cognitive decline is expected to grow. Effective treatment of memory disorders is lacking, and novel pharmacological approaches are necessary. Despite a burgeoning body of research dedicated to the study of memory and its dysfunction in disease states, details behind the molecular regulation of memory remains elusive. Recent studies point to a novel function of epigenetic mechanisms in memory formation. Epigenetics has traditionally been described as a set of heritable molecular mechanisms that stably influence gene expression; these reports indicate the largely postmitotic brain has co-opted these processes for both dynamic and persistent regulation of transcription. Investigations into neuronal activity- dependent methylation of DNA at cytosine bases and covalent modification of histones, core chromatin constituents closely apposed to DNA, confirm functional roles of these mechanisms in memory formation. DNA methyltransferases catalyze active DNA methylation, but virtually no consistent evidence existed for a molecular regulator of the reverse reaction. Two recent studies, however, uncover the role of the Growth arrest and DNA damage-inducible protein 45 (Gadd45) family in DNA demethylation. Notably, the expression of the beta isoform responds to neuronal depolarization in the hippocampus, a brain region critical to memory processing. The function of Gadd45b as a mediator of DNA demethylation and as an immediate early gene suggests that it potentially induces DNA demethylation in memory formation. The purpose of this research proposal is to study the contribution of Gadd45b in hippocampus-dependent memory formation. A genetic approach using mice with engineered deletion of the gadd45b locus will be employed to address this question. To study the function of Gadd45b in memory formation, wildtype and mutant mice will be assessed in a behavioral battery designed to study memory and baseline behavior. Long-term memory consolidation is subserved by lasting changes in synaptic efficacy, a phenomenon known as synaptic plasticity. To study the function of Gadd45b in hippocampal long-term potentiation, hippocampal recordings from both genotypes will be taken. Further studies are designed to study the genetic targets of Gadd45b-mediated demethylation. Pharmacological induction of DNA demethylation in slices will be performed to gauge putative targets. Finally, an in vivo approach will be taken; animals will be trained in an associative memory task, and epigenetic regulation of gene expression in the hippocampus will be studied. Preliminary data indicate a suppressive function of Gadd45b in memory consolidation. This suggests DNA methylation and demethylation perform opposing functions not only in molecular processes but also in behavior. The proposed study is designed to investigate the breadth of the ethological, physiological and molecular role of DNA demethylation in further detail.

项目摘要 在美国，记忆障碍仍然是一个主要的医疗负担。随着人口老龄化， 与衰老相关的认知功能减退的患病率预计还会增加。有效治疗记忆 疾病是缺乏的，新的药理学方法是必要的。尽管有一大批 致力于研究疾病状态下记忆及其功能障碍的研究，分子背后的细节 对记忆的调控仍然难以捉摸。最近的研究指出了表观遗传机制的一种新功能 记忆的形成。表观遗传学传统上被描述为一套可遗传的分子机制 稳定地影响基因表达；这些报告表明，大部分有丝分裂后的大脑已经吸收了这些 转录的动态和持续调节过程。对神经元活动的研究- DNA胞嘧啶碱基的依赖甲基化和组蛋白、核心染色质的共价修饰 与DNA密切相反的成分，证实了这些机制在记忆形成中的功能作用。脱氧核糖核酸 甲基转移酶催化活性DNA甲基化，但几乎没有一致的证据表明 逆反应的分子调节剂。然而，最近的两项研究揭示了增长停滞的作用 DNA去甲基化中的DNA损伤诱导蛋白45(GADD45)家族。值得注意的是， 贝塔异构体对大脑记忆关键区域--海马区的神经元去极化作出反应 正在处理。Gadd45b作为DNA去甲基化介质和即刻早期基因的功能 这表明它可能会诱导记忆形成中的DNA去甲基化。这项研究的目的是 建议研究Gadd45b在海马体依赖记忆形成中的作用。一种基因 使用gadd45b基因座工程缺失的小鼠的方法将被用来解决这个问题。 为了研究Gadd45b在记忆形成中的作用，野生型和突变小鼠将在 用于研究记忆和基线行为的行为电池。长期的记忆巩固是 伴随着突触效力的持久变化，这种现象被称为突触可塑性。为了研究 Gadd45b在海马长时程增强中的作用，两种基因的海马区记录将 被带走了。进一步的研究旨在研究Gadd45b介导的去甲基化的遗传靶点。 将在切片中进行DNA去甲基化的药物诱导，以确定可能的靶点。最后， 将采取活体方法；动物将在联想记忆任务中接受训练，并进行表观遗传学 海马区基因表达的调控将被研究。初步数据显示， Gadd45b在内存整合中的作用。这表明DNA甲基化和去甲基化执行 对立不仅在分子过程中起作用，而且在行为中也起作用。这项拟议的研究旨在 进一步研究DNA去甲基化在行为学、生理学和分子方面的广泛作用 细节。