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

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(由申请人提供):一种共识正在形成,即几种癫痫疾病,包括颞叶癫痫(TLE),一种部分成人发作的人类癫痫,通常与显著的长期认知障碍相关。目前,还没有有效的治疗方案来预防或逆转癫痫相关的记忆丧失,潜在的分子机制仍然难以捉摸。我们实验室和其他人最近的工作涉及癫痫中异常的表观遗传DNA甲基化(DNAme)调节。因此,我们建议,DNAme可能是一个主要的贡献者在癫痫海马异常基因转录。因为,以前的研究表明,脑源性神经营养因子(Bdnf)基因的表达是记忆形成所必需的,并且在癫痫患者和自发性癫痫大鼠的海马中显著失调,我们将通过调查TLE记忆形成过程中海马兴奋性突触中Bdnf的表观遗传调节来集中我们的研究。有趣的是,表观遗传学在介导癫痫海马中行为诱导的BDNF基因表达变化中的作用在很大程度上是未知的。我们将在我们的TLE实验模型中使用DNMT抑制剂和Methylene操纵DNAme,以深入了解治疗癫痫相关记忆丧失的潜在治疗靶点。由于这些抑制剂已经在临床上使用或正在积极研究和开发的肿瘤学,有可能迅速转化为治疗癫痫相关的记忆障碍和其他合并症,如抑郁症和焦虑症的人类。这个建议的中心假设是,异常DNAme介导的转录调控的记忆允许基因,如BDNF,在癫痫海马有助于癫痫相关的记忆障碍。使用新的方法和技术途径,本建议的目的如下:1)测试在TLE的实验啮齿动物模型中,在记忆形成期间,在CA1锥体神经元中通过DNAme的BDNF基因调节是否改变,和2)测试用甲硫氨酸治疗是否逆转TLE中的两种癫痫表型、海马网络过度活跃和海马依赖性记忆形成。了解与TLE相关的记忆缺陷的病理生理机制,在细胞和分子水平和潜在的治疗策略的评估无疑优先在与这种神经系统疾病相关的认知障碍的研究路径。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Farah Dominique Lubin其他文献

Farah Dominique Lubin的其他文献

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{{ truncateString('Farah Dominique Lubin', 18)}}的其他基金

The role of IncRNA Neat1 in Alzheimer's disease and related memory deficits
IncRNA Neat1 在阿尔茨海默病和相关记忆缺陷中的作用
  • 批准号:
    10666025
  • 财政年份:
    2023
  • 资助金额:
    $ 18.38万
  • 项目类别:
Long Non-coding RNA Regulation in Astrocytes within the Aging Brain
衰老大脑中星形胶质细胞的长非编码RNA调控
  • 批准号:
    10195946
  • 财政年份:
    2021
  • 资助金额:
    $ 18.38万
  • 项目类别:
Long Non-coding RNA Regulation in Astrocytes within the Aging Brain
衰老大脑中星形胶质细胞的长非编码RNA调控
  • 批准号:
    10392421
  • 财政年份:
    2021
  • 资助金额:
    $ 18.38万
  • 项目类别:
Long Non-coding RNA Regulation in Astrocytes within the Aging Brain
衰老大脑中星形胶质细胞的长非编码RNA调控
  • 批准号:
    10602434
  • 财政年份:
    2021
  • 资助金额:
    $ 18.38万
  • 项目类别:
UAB Neuroscience Roadmap Scholars Program
UAB 神经科学路线图学者计划
  • 批准号:
    9923216
  • 财政年份:
    2019
  • 资助金额:
    $ 18.38万
  • 项目类别:
Epigenetic Mechanisms in Epilepsy-Related Memory Formation
癫痫相关记忆形成的表观遗传机制
  • 批准号:
    8969271
  • 财政年份:
    2015
  • 资助金额:
    $ 18.38万
  • 项目类别:
UAB Neuroscience Roadmap Scholars Program
UAB 神经科学路线图学者计划
  • 批准号:
    8793893
  • 财政年份:
    2014
  • 资助金额:
    $ 18.38万
  • 项目类别:
UAB Neuroscience Roadmap Scholars Program
UAB 神经科学路线图学者计划
  • 批准号:
    10474395
  • 财政年份:
    2014
  • 资助金额:
    $ 18.38万
  • 项目类别:
UAB Neuroscience Roadmap Scholars Program
UAB 神经科学路线图学者计划
  • 批准号:
    9321259
  • 财政年份:
    2014
  • 资助金额:
    $ 18.38万
  • 项目类别:
UAB Neuroscience Roadmap Scholars Program
UAB 神经科学路线图学者计划
  • 批准号:
    10024945
  • 财政年份:
    2014
  • 资助金额:
    $ 18.38万
  • 项目类别:

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