Epigenetic Regulation of Hippocampal Synaptic Plasticity

海马突触可塑性的表观遗传调控

• 批准号: 8430430
• 负责人: Morgan Stuart Bridi
• 金额: $ 4.22万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8430430
• 关键词: Acute; Affect; Aging; Behavioral; Binding; Binding Proteins; Cell Culture Techniques; Chemosensitization; Cognition Disorders; Complex; Cyclic AMP-Responsive DNA-Binding Protein; Data; Disease; Dominant-Negative Mutation; Enzymes; Epigenetic Process; Event; Family; Fright; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Genome; Goals; HDAC1 gene; HDAC2 gene; Hereditary Disease; Hippocampus (Brain); Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Histones; Immediate-Early Genes; Knockout Mice; Knowledge; Learning; Link; Memory; Memory impairment; Mental disorders; Molecular; Molecular Profiling; Mus; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Nuclear Receptors; Pathway interactions; Process; Promoter Regions; Protein Binding; Protein Biosynthesis; Proteins; Recruitment Activity; Regulation; Repression; Repressor Proteins; Research; Research Support; Role; Site; Slice; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Training; Transcriptional Activation; Transcriptional Regulation; Western Blotting; Work; base; chromatin immunoprecipitation; cognitive function; disorder control; gene repression; histone acetyltransferase; long term memory; mouse model; nervous system disorder; novel strategies; novel therapeutic intervention; prevent; promoter; protein complex; research study; response; tool; transcription factor

DESCRIPTION (provided by applicant): The consolidation of long-term memory and the formation of long-term synaptic potentiation both require gene transcription and de novo protein synthesis. Multiple systems regulate these transcriptional events, offering several points of control over learning processes. Recent work from our lab and others has demonstrated a crucial role for epigenetic mechanisms in learning and plasticity, and this work has revealed links between disruption of epigenetic control and disorders of cognition. Inhibiting histone deacetylase (HDAC) enzymes enhances normal memory and rescue impairments of memory in mouse models of disease. Although this manipulation of the epigenetic regulation of transcription shows promise as a therapeutic tool, the underlying mechanisms of how it functions are unknown. Sin3a is a co-repressor protein that recruits HDAC enzymes to gene promoters to maintain their repression through histone hypoacetylation. The nuclear receptor subfamily 4 (Nr4a) transcription factors, regulated via histone acetylation by the cyclic AMP response element binding protein (CREB) and the co-activator CREB-binding protein (CBP), are also strong candidates for negative regulation by the Sin3a/HDAC complex. The Nr4a family of immediate early genes is transcribed immediately after neuronal activation, and the NR4A proteins are known to regulate the transcription of many genes important for memory and plasticity. I propose here to investigate in parallel the roles of Sin3a and the Nr4a transcription factors in hippocampal synaptic plasticity, and to uncover the identity of their regulatory targets in the hippocampal genome.

描述（由申请人提供）：长期记忆的巩固和长期突触增强的形成都需要基因转录和从头蛋白质合成。多个系统调节这些转录事件，为学习过程提供了几个控制点。我们实验室和其他人最近的工作已经证明了表观遗传机制在学习和可塑性中的关键作用，这项工作揭示了表观遗传控制中断与认知障碍之间的联系。抑制组蛋白去乙酰化酶（HDAC）酶增强正常记忆并挽救疾病小鼠模型中的记忆损伤。尽管这种对转录的表观遗传调控的操纵显示出作为治疗工具的希望，但其如何发挥作用的潜在机制尚不清楚。Sin 3a是一种共阻遏蛋白，其通过组蛋白低乙酰化将HDAC酶募集到基因启动子以维持其阻遏。核受体亚家族4（Nr 4a）转录因子，通过环AMP反应元件结合蛋白（CREB）和共激活剂CREB结合蛋白（CBP）通过组蛋白乙酰化调节，也是Sin 3a/HDAC复合物负调节的强有力的候选者。立即早期基因的Nr 4a家族在神经元激活后立即转录，并且已知NR 4A蛋白调节对记忆和可塑性重要的许多基因的转录。我建议在这里平行调查的Sin 3a和Nr 4a转录的作用 海马突触可塑性的因素，并揭示其调控目标的身份 在海马基因组中。