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：
8760440
负责人：
JEANNIE CHIN
金额：
$ 35.2万
依托单位：
THOMAS JEFFERSON UNIVERSITY
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/8760440
关键词：
Acute Address Alzheimer&apos s Disease Alzheimer&apos s disease model Benchmarking Binding Brain Injuries Brain Part Brain region Chronic Cognition Cognitive deficits Comorbidity Data Deacetylation Development Disease Dominant-Negative Mutation Environment Epigenetic Process Epilepsy Event Exhibits Exposure to FOS gene Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Goals Half-Life Health Hippocampus (Brain)Histone Deacetylase Histone Deacetylase Inhibitor Immediate-Early Genes Impaired cognition Knowledge Lead Mediating Memory Memory Loss Memory impairment Methylation Modeling Modification Molecular Molecular Profiling Mus Neurologic Neurons Nuclear Pathway interactions Play Promoter Regions Recurrence Repression Research Role Seizures Severities Synaptic plasticity Testing Therapeutic Therapeutic Intervention Transgenic Mice Transgenic Organisms Viral Wild Type Mouse chromatin immunoprecipitation chromatin modification cognitive function drug of abuse forging granule cell improved information processing insight kainate mouse model novel novel therapeutic intervention overexpression prevent promoter 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 ΔFosB 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 ΔFosB that exerted long lasting epigenetic repression of gene expression, with detrimental consequences for hippocampal-dependent spatial memory. Such increases in ΔFosB 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 mechanisms by which ΔFosB 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 investigate the expression profiles of ΔFosB expression and severity of cognitive deficits in kainate and AD mice with varying seizure severity; we will also determine whether overexpression of ΔFosB is sufficient to induce cognitive deficits. In Aim 2, we will identify the mechanisms by which ΔFosB 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 ΔFosB blocks ΔFosB'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，癫痫引起的海马转录因子 ΔFosB 表达增加会引发一系列导致表观遗传抑制的事件。海马体中的许多基因，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 ΔFosB 的表达增加，从而对基因表达产生持久的表观遗传抑制，从而对海马依赖性空间产生影响。在癫痫的药理学红藻氨酸模型以及癫痫的转基因小鼠模型中观察到这种 ΔFosB 表达的增加、表观遗传改变和相关的空间记忆缺陷。阿尔茨海默病 (AD)，两者均表现出反复发作，该提案的目标是确定 ΔFosB 诱导突触可塑性所需关键基因的表观遗传抑制的机制，以及正常化基因表达是否可以恢复红藻氨酸和 AD 模型的认知功能。为了实现这些目标，在目标 1 中，我们将研究不同癫痫发作严重程度的红藻氨酸和 AD 小鼠的 ΔFosB 表达谱和认知缺陷的严重程度；确定 ΔFosB 的过度表达是否足以诱导认知缺陷在目标 2 中，我们将确定 ΔFosB 诱导调节红藻氨酸和 AD 小鼠基因表达的染色质修饰的机制。 ΔFosB 的负拮抗剂可阻断 ΔFosB 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。理解反复发作如何损害认知功能的新途径，并强调了治疗靶向的新途径。此外，它们将为任何与反复发作相关的疾病（例如 AD）的认知障碍的常见机制提供新的见解。多种神经系统疾病/疾病的共病，我们的研究结果将产生广泛的影响。