Chromatin Remodeling and Memory Storage

染色质重塑和记忆存储

基本信息

批准号：
8060657
负责人：
Marcelo Andres Wood
金额：
$ 41.53万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-11 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8060657
关键词：
Abbreviations Acute Address Affect Attention Binding Proteins CREB-binding protein Chromatin Chronic Clinical Code Cognition Disorders Cyclic AMP Response Element Cyclic AMP-Responsive DNA-Binding Protein DNA DNA Packaging Data Drug Addiction Enzymes Epigenetic Process Essential Genes Exhibits Gene Expression Gene Expression Regulation Genes Genetic Transcription Hippocampus (Brain)Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histones Human Huntington Disease Impaired cognition Impairment Individual Investigation Knock-in Mouse Memory Mental Depression Mental Retardation Molecular Mus Mutant Strains Mice Neurodegenerative Disorders Neurons Orphan Nuclear Receptor Gene Pharmaceutical Preparations Protein Binding Regulation Research Research Proposals Retrieval Role Rubinstein-Taybi Syndrome Schizophrenia Sodium Butyrate Staging Synaptic plasticity Therapeutic Therapeutic Agents Transcription Coactivator Transcriptional Regulation Transgenic Organisms Trichostatin A Work chromatin remodeling cofactor conditioned fear histone acetyltransferase histone modification human CREBBP protein inhibitor/antagonist long term memory memory acquisition memory process mutant programs promoter protein complex protein expression public health relevance research study small molecule transcription factor

项目摘要

DESCRIPTION (provided by applicant): It has long been appreciated that gene transcription is required for long-term memory storage, but only recently has it become clear that transcriptional regulation for memory processes involves the concerted action of multiple transcription factors and coactivators that interact with chromatin, a protein complex that packages DNA. Originally thought to be static and structural in purpose, chromatin is now known to be very dynamic, exerting precise control over gene expression. The idea that chromatin remodeling may regulate gene expression for memory processes has gained considerable attention recently through the study of enzymes that are involved in chromatin remodeling, in particular, histone acetyltransferases (HATs) and histone deacetylases (HDACs). For example, our previous research demonstrated that CREB-binding protein (CBP), a potent HAT and transcriptional coactivator, is critical for long-lasting forms of synaptic plasticity (the activity- dependent change in the strength of neuronal connections) and long-term memory. In this proposed research program, we continue to examine our central hypothesis that enzymes involved in chromatin remodeling are essential for gene expression involved in memory processes. Our preliminary data demonstrate that HDAC inhibitors (small molecule antagonists that block HDAC activity and induce a histone hyper-acetylated state) enhance synaptic plasticity and memory storage. Further, we find that HDAC inhibitors enhance memory processes via a defined molecular mechanism. To examine the effect of HDAC inhibitors on memory storage and define the molecular mechanism underlying the modulation of memory storage by HDAC inhibitors we propose three specific aims. In specific aim 1, we will examine how HDAC inhibition affects memory. In specific aim 2, we will define the underlying molecular mechanism by which HDAC inhibition enhances memory. In specific aim 3, we will examine how chromatin remodeling regulates gene expression during memory consolidation. Results from these experiments promise to significantly contribute to our understanding of how chromatin remodeling via histone modification regulates gene expression required for long-lasting forms of memory. Chromatin remodeling is considered a form of `epigenetic' regulation, in which gene expression is regulated without altering the DNA code, and may have long-lasting effects. Sustained epigenetic mechanisms of gene regulation in neurons have recently become central to several cognitive disorders including mental retardation, depression, and schizophrenia. PUBLIC HEALTH RELEVANCE: It has become clear that transcriptional regulation for memory processes involves the concerted action of multiple transcription factors and coactivators that interact with chromatin, a protein complex that packages DNA. Chromatin remodeling is considered a form of `epigenetic' regulation, in which gene expression is regulated without altering the DNA code, and may have long-lasting effects, an idea that has become central to understanding the molecular mechanisms underlying several cognitive disorders including mental retardation, depression, and schizophrenia. The experiments in this research proposal are focused on understanding how chromatin remodeling regulates gene expression required for memory processes.

描述（由申请人提供）：长期以来，长期记忆存储需要基因转录，但直到最近才清楚地表明，记忆过程的转录调控涉及多种转录因子的一致作用和与染色质相互作用的共同激活剂的协同作用，这是一种包装DNA的蛋白质复合物。最初被认为是目的的静态和结构性的，现在已知染色质是非常动态的，可以精确控制基因表达。最近，通过研究与染色质重塑有关的酶，特别是组蛋白乙酰基转移酶（HATS）和组蛋白脱乙酰基酶（HDACS）（HDACS），染色质重塑可能调节基因表达的记忆过程基因表达。例如，我们先前的研究表明，CREB结合蛋白（CBP）是一种有效的帽子和转录共激活因子，对于长期突触可塑性（神经元连接强度的活性变化）和长期记忆的长期形式至关重要。在该提出的研究计划中，我们继续研究中心假设，即参与染色质重塑的酶对于参与记忆过程的基因表达至关重要。我们的初步数据表明，HDAC抑制剂（阻断HDAC活性并诱导组蛋白高乙酰化状态的小分子拮抗剂）增强突触可塑性和记忆存储。此外，我们发现HDAC抑制剂通过定义的分子机制增强了记忆过程。为了检查HDAC抑制剂对存储器存储的影响，并定义了HDAC抑制剂调节存储器存储的基础机制，我们提出了三个特定的目标。在特定目标1中，我们将研究HDAC抑制如何影响记忆。在特定目标2中，我们将定义HDAC抑制增强记忆的潜在分子机制。在特定的目标3中，我们将研究染色质重塑如何调节记忆巩固过程中的基因表达。这些实验的结果有望显着有助于我们理解通过组蛋白修饰的染色质重塑如何调节长期记忆形式所需的基因表达。染色质重塑被认为是“表观遗传”调节的一种形式，其中基因表达在不改变DNA代码的情况下受到调节，并且可能具有长期效果。神经元中基因调节的持续表观遗传机制最近已成为多种认知障碍的核心，包括智力低下，抑郁症和精神分裂症。公共卫生相关性：很明显，记忆过程的转录调节涉及多种转录因子和与染色质相互作用的共同激活剂的协同作用，这些转录因子是一种包装DNA的蛋白质复合物。染色质重塑被认为是“表观遗传”调节的一种形式，其中基因表达在不改变DNA代码的情况下受到调节，并且可能具有长期的效果，这一想法已成为理解几种认知障碍的分子机制的核心，包括精神障碍，抑郁症，抑郁症和精神病。该研究建议中的实验侧重于了解染色质重塑如何调节记忆过程所需的基因表达。