The histone code of neuronal function and dysfunction

神经元功能和功能障碍的组蛋白密码

• 批准号: 9353876
• 负责人: Erica Megan Korb
• 金额: $ 12.71万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2018-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353876
• 关键词: Acetylation; Affect; Award; Behavioral; Biochemical; Brain; Brain Diseases; Cells; Chromatin; Collaborations; Complex; DNA; Data; Development; Disease; Enzymes; Epigenetic Process; Excision; FMR1; Foundations; Fragile X Syndrome; Functional disorder; Gene Activation; Gene Expression; Genes; Genetic Transcription; Genome; Genomics; Goals; Histone Acetylation; Histone Code; Histones; Information Storage; Laboratories; Language; Learning; Link; Memory; Mental Health; Mental disorders; Mentors; Methylation; Modification; Nervous System Physiology; Nervous System control; Nervous system structure; Neurodevelopmental Disorder; Neuronal Dysfunction; Neurons; Neurosciences; Output; Phase; Phosphorylation; Positioning Attribute; Post-Translational Protein Processing; Process; Proteins; Regulation; Research; Role; Signal Transduction; Site; Synapses; Techniques; Training; Transcription Process; Transcriptional Regulation; Variant; Work; base; chromatin protein; developmental disease; epigenetic regulation; histone modification; inhibitor/antagonist; insight; mouse model; nervous system disorder; novel strategies; olfactory bulb; response; skills; synaptogenesis; tool

Project Summary A fundamental challenge in the field of neuroscience is understanding the link between environmental signals and the transcriptional response underlying the resulting long term changes in neuronal function. Neurons uniquely require highly dynamic and temporal control of gene activation for processes ranging from memory formation to synapse formation during development. Whether specific genes are ultimately activated is highly dependent on the epigenetic regulation of transcription through the histone proteins that control DNA accessibility and regulate transcription. The importance of this `histone code' or is becoming increasingly appreciated in neuroscience, from its function in memory storage to its involvement in neurological disorders. My goal is to elucidate the histone code that controls the nervous system with the aim of better understanding the regulation of transcription both in normal neurons and in mental and developmental disorders. The research I propose encompasses all aspects of histone regulation and has a strong foundation in the work developed and performed in the Allis laboratory on histone modifications and variants. During the training period, I will continue my work on the role of histone misregulation in neurodevelopmental disorders and the possibility of targeting this to alleviate neuronal dysfunction. I will also investigate the role of a new discovered histone variant linked to the transcriptional response to synaptic activity. Finally, I will begin to investigate the role of histone modifications such as crotonylation that have not yet been examined the context neuronal gene expression but provide the complex transcriptional regulation needed to achieve the varied functions of the nervous system. During this mentored period, I propose to develop and expand on new tools I will use to during the independent phase of the award. In addition, I will learn a combination of computational and genomics techniques and biochemical approaches that will set me apart from the field and provide me with the skills necessary to work at the intersection of epigenetics and neuroscience. With the development of new tools and acquisition of valuable skills that I describe in the training plan of award, I will be a unique position to apply diverse approaches to reveal new insights into the role of histones in regulating transcription of genes critical for neuronal function. This research will allow for the histone code of gene activation to be applied to information storage in the brain, providing new insights into mechanism underlying neuronal function and the epigenetic causes of neurological disorders.

项目摘要 神经科学领域的一个基本挑战是理解环境信号之间的联系 以及导致神经元功能长期变化的转录反应。神经元 独特地需要高度动态和时间控制基因激活的过程， 在发育过程中形成突触。特定的基因最终是否被激活是高度敏感的。 依赖于通过控制DNA的组蛋白对转录的表观遗传调节 可及性和调节转录。这种“组蛋白密码”的重要性正变得越来越重要， 它在神经科学中受到广泛的重视，从它在记忆存储中的功能到它在神经系统疾病中的作用。 我的目标是阐明控制神经系统的组蛋白密码， 在正常神经元和精神发育障碍中的转录调节。的 我建议的研究涵盖组蛋白调控的所有方面，并在工作中有坚实的基础 在Allis实验室开发并进行的关于组蛋白修饰和变体的研究。培训期间 在此期间，我将继续研究组蛋白失调在神经发育障碍中的作用， 有可能以此为靶点来缓解神经元功能障碍。我还将研究一种新发现的 组蛋白变体与突触活动的转录反应有关。最后，我将开始调查 组蛋白修饰的作用，如巴豆酰化，尚未被检查的背景神经元基因 表达，但提供了复杂的转录调控需要实现的各种功能， 神经系统在这段指导期间，我建议开发和扩展新工具， 在颁奖的独立阶段。此外，我将学习计算和 基因组学技术和生物化学方法，这将使我从外地除了，并为我提供 在表观遗传学和神经科学的交叉点工作所需的技能。与开发新 工具和收购有价值的技能，我在奖励的培训计划中描述，我将是一个独特的位置， 应用不同的方法来揭示组蛋白在调节基因转录中的作用的新见解 对神经元功能至关重要这项研究将允许基因激活的组蛋白密码被应用于 信息存储在大脑中，提供了新的见解机制的神经元功能和 神经系统疾病的表观遗传原因。