Role of deltaFosB in epigenetic regulation of gene expression and cognition

deltaFosB 在基因表达和认知的表观遗传调控中的作用

• 批准号: 9174592
• 负责人: JEANNIE CHIN
• 金额: $ 33.36万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174592
• 关键词: Acute; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Benchmarking; Binding; Brain Injuries; Brain Part; Brain region; Chronic; Cognition; Cognitive deficits; Comorbidity; Deacetylation; Development; Disease; Dominant-Negative Mutation; Environment; Epigenetic Process; Epilepsy; Event; Exhibits; Exposure to; FOS gene; Frequencies; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Half-Life; Health; Hippocampus (Brain); Histone Deacetylase; Histone Deacetylase Inhibitor; Immediate-Early Genes; Impaired cognition; Incidence; Knowledge; Lead; Mediating; Memory; Memory Loss; Memory impairment; Methylation; Modeling; Molecular; Mus; Neurologic; Neurons; Nuclear; Pathway interactions; Play; Promoter Regions; Recurrence; Repression; Research; Role; Seizures; Severities; Synaptic plasticity; Therapeutic; Therapeutic Intervention; Transgenic Mice; Viral; Work; chromatin immunoprecipitation; chromatin modification; cognitive function; drug of abuse; epigenetic regulation; forging; gene repression; granule cell; improved; information processing; insight; kainate; mouse model; novel; prevent; promoter; spatial memory; therapeutic target; therapy design; transcription factor

DESCRIPTION (provided by applicant): Cognitive impairment is a devastating co-morbidity of epilepsy. However, the molecular mechanisms by which recurrent seizures induce cognitive impairments that persist even in seizure-free periods are not well understood. This gap in knowledge hampers the development of therapeutic interventions to reduce cognitive deficits associated with epilepsy. Our preliminary studies demonstrate that seizure-induced increase in hippocampal expression of the transcription factor �FosB triggers a chain of events leading to epigenetic repression of a number of genes in the hippocampus, some of which are known to be critical for the induction of synaptic plasticity. Increasing seizure severity led to increasing expression of �FosB that exerted long lasting epigenetic repression of gene expression, with detrimental consequences for hippocampal-dependent spatial memory. Such increases in �FosB expression, epigenetic alterations, and associated spatial memory deficits were observed in a pharmacological kainate model of epilepsy as well as a transgenic mouse model of Alzheimer's disease (AD), both of which exhibit recurrent seizures. The goals of this proposal are to determine the precise mechanisms by which �FosB induces epigenetic repression of key genes required for synaptic plasticity, and whether normalizing gene expression restores cognitive function in kainate and AD models with recurrent seizures. To achieve these goals, in Aim 1 we will characterize the dynamics of �FosB expression, downstream gene repression, and cognitive deficits in kainate and AD mice. In Aim 2, we will determine the mechanisms by which �FosB induces chromatin modifications that regulate gene expression in kainate and AD mice. In Aim 3, we will determine whether viral expression of a dominant negative antagonist of �FosB blocks �FosB's effects on gene expression in the hippocampus, and restores cognitive function in kainate and AD mice. Results from these studies will forge a new avenue of understanding how recurrent seizures impair cognitive function, and highlight a novel pathway for therapeutic targeting. In addition, they will provide novel insights into common mechanisms of cognitive impairment in any condition associated with recurrent seizures, such as AD. Given that epilepsy is a co-morbidity of a number of neurological conditions/diseases the results from our studies will have broad impact.

描述（由申请人提供）：认知障碍是癫痫的一种破坏性共病。然而，反复发作导致认知障碍（即使在无癫痫发作期间也持续存在）的分子机制尚不清楚。这种知识差距阻碍了减少癫痫相关认知缺陷的治疗干预措施的发展。我们的初步研究表明，癫痫发作引起的海马转录因子 FosB 表达增加会触发一系列事件，导致海马中许多基因的表观遗传抑制，其中一些基因对于诱导突触可塑性至关重要。癫痫发作严重程度的增加导致 �FosB 的表达增加，从而对基因表达产生持久的表观遗传抑制，对海马依赖性空间记忆产生有害后果。在癫痫药理学红藻氨酸模型和阿尔茨海默病 (AD) 转基因小鼠模型中观察到这种 FosB 表达、表观遗传改变和相关空间记忆缺陷的增加，这两种模型都表现出反复发作。该提案的目标是确定 FosB 诱导突触可塑性所需关键基因的表观遗传抑制的精确机制，以及基因表达正常化是否可以恢复红藻氨酸和反复发作的 AD 模型的认知功能。为了实现这些目标，在目标 1 中，我们将描述红藻氨酸和 AD 小鼠的 FosB 表达动态、下游基因抑制和认知缺陷。在目标 2 中，我们将确定 FosB 诱导染色质修饰调节红藻氨酸和 AD 小鼠基因表达的机制。在目标 3 中，我们将确定 ?FosB 的显性负拮抗剂的病毒表达是否会阻断 ?FosB 对海马基因表达的影响，并恢复红藻氨酸和 AD 小鼠的认知功能。这些研究的结果将为理解反复发作如何损害认知功能开辟一条新途径，并强调治疗靶向的新途径。此外，他们还将为任何与复发性癫痫发作相关的疾病（例如 AD）中认知障碍的常见机制提供新颖的见解。鉴于癫痫是许多神经系统疾病/疾病的共病，我们的研究结果将产生广泛的影响。