Modeling Gene Regulation Essential for Long-Term Plasticity

对长期可塑性至关重要的基因调控建模

• 批准号: 8258707
• 负责人: John H Byrne
• 金额: $ 29.53万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258707
• 关键词: ATF2 gene; Accounting; Acetylation; Address; Affect; Animals; Aplysia; Behavior; Biochemical Genetics; Biochemical Process; Brain Diseases; CCAAT-Enhancer-Binding Proteins; CREB1 gene; Chromatin; Coffin-Lowry syndrome; Cognition; Cognitive; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Development; Disease; Elements; Equation; Event; Family; Feedback; Gene Expression Regulation; Gene Proteins; Genetic; Genetic Processes; Genetic Transcription; Goals; Hippocampus (Brain); Human; Impaired cognition; Impairment; Invertebrates; Lead; Learning; Long-Term Potentiation; Mammals; Mediating; Memory; Memory impairment; Messenger RNA; Methods; MicroRNAs; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Target; Mutation; Neurofibromatoses; Neurofibromatosis 1; Neurons; Nuclear; Pharmacological Treatment; Phosphorylation; Phosphotransferases; Physiological; Play; Process; Protein Isoforms; Protein Kinase M; Proteins; Protocols documentation; Pyramidal Cells; Regulation; Relative (related person); Rodent; Role; Rubinstein-Taybi Syndrome; Signal Pathway; Signal Transduction; Simulate; Site; Stimulus; Study models; Synapses; Synaptic plasticity; System; Testing; Training; Transcription Repressor/Corepressor; Transcriptional Activation; Transcriptional Regulation; Vertebrates; base; cognitive function; computer studies; gene repression; long term memory; mathematical model; novel; public health relevance; simulation; transcription factor

DESCRIPTION (provided by applicant): Learning and memory are cornerstones of human cognition, and cognitive defects are associated with many brain disorders. It has recently become possible to relate cognitive function to specific molecules. These molecules include the CREB family of transcription factors, which are essential for long-term (LT) synaptic plasticity and memory. Alterations in CREB signaling pathways are associated with diseases that impair cognition, such as Rubinstein-Taybi syndrome, neurofibromatosis, and Coffin-Lowry syndrome. Many of the molecular details of these signaling pathways are known. However, the ways in which these elements quantitatively account for normal and pathological cellular behavior are not well understood because the signaling cascades are embedded in a biochemical and genetic network that includes extensive cross talk and negative and positive feedback loops. To address this issue, the present proposal outlines computational studies that model and simulate CREB signaling pathways and their role in memory. Two well characterized neuronal correlates of memory will be modeled: long-term facilitation (LTF) and long-term potentiation (LTP). The proposed models will use differential equations to simulate molecular processes and will be constrained by empirical data. Aim 1 will test the hypothesis that the dynamics for the induction and consolidation of LTF are governed by the dynamics of the PKA and ERK kinase cascades and by feedback loops within CREB regulated transcription. Simulations will examine the efficacy of training protocols and predict protocols that optimize learning. Aim 2 will test the hypothesis that LTF and LTP share molecular mechanisms and dynamics. Simulations will identify control parameters, which may correspond to pharmacological control points for enhancing learning and cognition. Simulations also will explore LT plasticity impairment due to mutations that affect CREB activity, such as Rubinstein-Taybi syndrome. Finally, the models will be used to predict treatments for ameliorating CREB-related memory deficits and thereby help restore normal plasticity, learning and memory. PUBLIC HEALTH RELEVANCE: Learning and memory are essential to human cognition, and their disruptions contribute to several brain diseases including neurofibromatosis, Rubinstein-Taybi syndrome, and Coffin-Lowry syndrome. This project will advance the understanding of basic memory mechanisms, which will lead to better learning paradigms and help identify molecular targets for pharmacological treatments of brain disorders.

描述（由申请人提供）：学习和记忆是人类认知的基石，认知缺陷与许多大脑疾病有关。最近，将认知功能与特定分子联系起来已成为可能。这些分子包括 CREB ​​转录因子家族，它们对于长期 (LT) 突触可塑性和记忆至关重要。 CREB ​​信号通路的改变与损害认知的疾病有关，例如 Rubinstein-Taybi 综合征、神经纤维瘤病和 Coffin-Lowry 综合征。这些信号传导途径的许多分子细节是已知的。然而，这些元素定量解释正常和病理细胞行为的方式尚不清楚，因为信号级联嵌入到生化和遗传网络中，其中包括广泛的串扰以及负反馈和正反馈回路。为了解决这个问题，本提案概述了模拟和模拟 CREB ​​信号通路及其在记忆中的作用的计算研究。将对记忆的两个明确表征的神经元相关性进行建模：长期促进（LTF）和长期增强（LTP）。 所提出的模型将使用微分方程来模拟分子过程，并将受到经验数据的约束。目标 1 将检验以下假设：LTF 的诱导和巩固的动力学受 PKA 和 ERK 激酶级联的动力学以及 CREB ​​调节转录内的反馈环控制。模拟将检查训练方案的有效性并预测优化学习的方案。目标 2 将检验 LTF 和 LTP 共享分子机制和动力学的假设。 模拟将识别控制参数，这些参数可能对应于增强学习和认知的药理学控制点。模拟还将探索由于影响 CREB ​​活性的突变（例如 Rubinstein-Taybi 综合征）导致的 LT 可塑性损伤。最后，这些模型将用于预测改善 CREB ​​相关记忆缺陷的治疗方法，从而帮助恢复正常的可塑性、学习和记忆。 公共健康相关性：学习和记忆对于人类认知至关重要，其破坏会导致多种脑部疾病，包括神经纤维瘤病、鲁宾斯坦-泰比综合征和科芬-洛瑞综合征。该项目将促进对基本记忆机制的理解，这将带来更好的学习范式，并有助于确定脑部疾病药物治疗的分子靶标。