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.