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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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，即使在无癫痫发作期间，反复发作导致认知障碍持续存在的分子机制尚不清楚，这一知识空白阻碍了发展。我们的初步研究表明，癫痫发作引起的海马转录因子 FosB 表达增加会引发一系列事件，导致表观遗传抑制。海马体中的许多基因，其中一些基因对于突触可塑性的诱导至关重要。癫痫发作严重程度的增加会导致 �FosB 的表达增加，从而对基因表达产生持久的表观遗传抑制，并对海马依赖性造成惩罚。在癫痫药理学红藻氨酸模型以及癫痫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。阿尔茨海默病 (AD) 均表现出复发性癫痫发作，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阿尔茨海默病的认知功能。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、下游基因抑制和认知缺陷的动态。 2，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 的显性失活拮抗剂的病毒表达是否会阻断 fosB 对基因表达的影响。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，并强调一条新途径。此外，鉴于癫痫是许多神经系统疾病/疾病的共病，他们将为任何与复发性癫痫发作相关的疾病的常见机制提供新的见解。研究将产生广泛的影响。