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: 9815713
• 负责人: Erica Megan Korb
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815713
• 关键词: Acetylation; Affect; Behavioral; Biochemical; Biology; 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; Investigation; Laboratories; Language; Learning; Link; Memory; Mental Health; Mental disorders; Methylation; Modification; Nervous System Physiology; Nervous System control; Nervous system structure; Neurodevelopmental Disorder; Neuronal Dysfunction; Neurons; Neurosciences; Output; Phosphorylation; Positioning Attribute; Process; Proteins; Regulation; Research; Research Personnel; Role; Signal Transduction; Site; Synapses; Syndrome; Techniques; Training; Transcription Process; Transcriptional Regulation; Variant; Work; base; chromatin protein; developmental disease; epigenetic regulation; histone modification; histone-binding proteins; 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 biology including histone binding proteins, histone modifications, and histone variants. I will build on my postdoctoral work by continuing to examine on the role of histone misregulation in neurodevelopmental disorders and the possibility of targeting this to alleviate neuronal dysfunction. I will also continue my investigation into the role of a new discovered histone variant linked to the transcriptional response to synaptic activity. Finally, I will examine 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. I will apply the tools and skills I learned during my training to the study of neuroscience. These skills ranging from biochemical approaches to computational and genomics techniques will set me apart from the field and provide me with the background necessary to work at the intersection of epigenetics and neuroscience. As I begin my work as independent investigator, 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.

项目概要： 神经科学领域的一个根本挑战是了解环境信号与导致神经元功能长期变化的转录反应之间的联系。神经元独特地需要高度动态和时间控制基因激活的过程，从记忆形成到发育过程中的突触形成。特定基因最终是否被激活高度依赖于通过控制DNA可及性和调节转录的组蛋白对转录的表观遗传调节。这种“组蛋白密码”的重要性在神经科学中越来越受到重视，从它在记忆储存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，目的是更好地理解正常神经元和精神发育障碍中的转录调控。我建议的研究包括组蛋白生物学的各个方面，包括组蛋白结合蛋白，组蛋白修饰和组蛋白变体。我将在博士后工作的基础上继续研究组蛋白失调在神经发育障碍中的作用，以及以此为目标减轻神经元功能障碍的可能性。我也将继续研究一种新发现的组蛋白变体的作用，这种变体与突触活动的转录反应有关。最后，我将研究组蛋白修饰的作用，如巴豆酰化，尚未检查上下文神经元基因表达，但提供了复杂的转录调控需要实现神经系统的各种功能。我将把我在培训期间学到的工具和技能应用到神经科学的研究中。从生物化学方法到计算和基因组学技术的这些技能将使我与该领域分开，并为我提供在表观遗传学和神经科学交叉点工作所需的背景。当我开始我作为独立研究者的工作时，我将是一个独特的位置，可以应用不同的方法来揭示组蛋白在调节对神经元功能至关重要的基因转录中的作用的新见解。这项研究将允许基因激活的组蛋白密码应用于大脑中的信息存储，为神经元功能的机制和神经系统疾病的表观遗传原因提供新的见解。