Epigenetic Mechanisms in Epilepsy-Related Memory Formation

癫痫相关记忆形成的表观遗传机制

基本信息

批准号：
8969271
负责人：
Farah Dominique Lubin
金额：
$ 22.05万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8969271
关键词：
Aberrant DNA Methylation Adult Amino Acids Animals Anxiety Behavioral Biochemical Biological Assay Brain Brain Diseases Brain region Brain-Derived Neurotrophic Factor Cerebellum Comorbidity Consensus DNA DNA Methylation DNA Methylation Regulation DNA Methyltransferase Inhibitor DNA Modification Methylases DNA methyltransferase inhibition Development Disease Drug Targeting Electroencephalography Enzymes Epigenetic Process Epilepsy Evaluation Excitatory Synapse Exons Experimental Models Functional disorder Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Transcription Hippocampus (Brain)Human Hyperactive behavior Impaired cognition Impairment Link Measures Mediating Memory Memory Loss Memory impairment Mental Depression Messenger RNA Methionine Methylation Methyltransferase Modeling Molecular Monitor Neuraxis Neurologic Neurons Pathogenesis Pathway interactions Patients Pharmacological Treatment Phenotype Process Proteins Rattus Regulation Regulator Genes Research Rodent Model Role Seizures Synaptic plasticity Temporal Lobe Epilepsy Testing Therapeutic Therapeutic Agents Therapeutic Intervention Tissues Training Transcriptional Regulation Translating Work base cognitive function effective therapy epigenetic regulation epigenome hippocampal pyramidal neuron inhibitor/antagonist insight kainate long term memory memory acquisition memory consolidation nervous system development nervous system disorder neuropathology novel oncology pre-clinical prevent public health relevance research study therapeutic target

项目摘要

DESCRIPTION (provided by applicant): A consensus is building that several epilepsy disorders, including Temporal lobe epilepsy (TLE), a partial adult onset form of human epilepsy, are often associated with significant long-term cognitive impairments. Currently, no effective treatment options exist to prevent or reverse epilepsy-related memory loss, and the underlying molecular mechanisms remain elusive. Recent work from our lab and others has implicated abnormal epigenetic DNA methylation (DNAme) regulation in epilepsy. Thus, we propose that DNAme may be a major contributor of aberrant gene transcription in the epileptic hippocampus. Because, previous studies have demonstrated that brain derived neurotrophic factor (Bdnf) gene expression is required for memory formation and is significantly dysregulated in the hippocampi of both epileptic patients and spontaneously seizing rats, we will focus our studies by investigating epigenetic regulation of Bdnf at excitatory synapses in the hippocampus during memory formation with TLE. Intriguingly, the role of epigenetics in mediating behaviorally- induced Bdnf gene expression changes in the epileptic hippocampus is largely uncharacterized. We will manipulate DNAme with DNMT inhibitors and Methionine in our experimental model of TLE, to gain insights into potential therapeutic targets for the treatment of epilepsy-related memory loss. Since these inhibitors are already in use clinically or being aggressively studied and developed in oncology, there is the potential to rapidly translate to treatments for epilepsy-related memory impairments and other comorbidities such as depression and anxiety in humans. The central hypothesis of this proposal is that aberrant DNAme mediated transcriptional regulation of memory permissive genes, like Bdnf, in the epileptic hippocampus contributes to epilepsy-related memory impairments. Using novel methodical and technical approaches, the aims of this proposal are as follows: 1) to test whether Bdnf gene regulation by DNAme is altered in CA1 pyramidal neurons during memory formation in an experimental rodent model of TLE, and 2) to test whether treatment with methionine reverses two-epileptic phenotypes, hippocampal network hyperactivity and hippocampus-dependent memory formation in TLE. Understanding the pathophysiological mechanisms of memory deficits associated with TLE at the cellular and molecular levels and evaluation of potential therapeutic strategies undoubtedly take priority in the path of research on cognitive impairments associated with this neurological disorder.

描述（由适用提供）：达成共识，即几种癫痫疾病，包括颞叶癫痫（TLE）是人类癫痫的部分成人发作形式，通常与重大的长期认知障碍有关。当前，尚无有效的治疗选择可以预防或逆转癫痫相关的记忆损失，并且潜在的分子机制仍然难以捉摸。我们实验室和其他人的最新工作已经实施了癫痫中异常表观遗传学DNA甲基化（DNAME）调节。因此，我们建议Dname可能是癫痫海马中异常基因转录的主要贡献者。因为，先前的研究表明，脑形成的脑衍生神经营养因子（BDNF）基因表达是必需的，并且在两位癫痫患者的海马中显着失调，并自发地抓住大鼠，我们将通过研究bdnf的表观遗传调节在Memory the Memory形成的bdnf中，通过研究BDNF的表观遗传调节来集中研究。有趣的是，表观遗传学在癫痫海马中介导行为诱导的BDNF基因表达变化中的作用在很大程度上没有表征。在我们的TLE实验模型中，我们将用DNMT抑制剂和甲硫氨酸来操纵DNAME，以洞悉潜在的治疗靶标，以治疗与癫痫相关的记忆丧失。由于这些抑制剂已经在临床上使用或积极研究并在肿瘤学上开发，因此有可能快速转化为癫痫相关记忆障碍的治疗，以及其他合并症，例如人类的抑郁症和焦虑。该提议的中心假设是，在癫痫海马中，异常的DNAME介导的记忆允许基因（如BDNF）的转录调控会导致与癫痫相关的记忆障碍。使用新颖的方法和技术方法，该提案的目的如下：1）测试在记忆形成期间CA1锥体神经元在记忆形成过程中是否改变了BDNF基因调节在TLE的实验啮齿动物模型中，以及2）以测试方法是否会依赖于两次发育现象的方法来测试是否会逆转2型抗态度。了解记忆的病理生理机制在细胞和分子水平上定义了与TLE相关的，并且对潜在的治疗策略的评估无疑是对与这种神经系统疾病相关的认知障碍的研究路径的优先级。