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: 8185497
• 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/8185497
• 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; 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，认知缺陷与许多脑部疾病有关。最近有可能将认知功能与特定分子联系起来。这些分子包括转录因子的Creb家族，这对于长期（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，神经纤维瘤病和棺材 - 洛里综合征。这些信号通路的许多分子细节都是已知的。然而，这些元素在定量上说明正常和病理细胞行为的方式尚未得到充分了解，因为信号级联反应嵌入了生化和遗传网络中，其中包括广泛的交叉谈话以及负面和正反馈循环。为了解决这个问题，本提案概述了对CREB信号通路及其在记忆中的作用进行建模和模拟的计算研究。将建模两个记忆的神经元相关性：长期促进（LTF）和长期增强（LTP）。 提出的模型将使用微分方程来模拟分子过程，并将受经验数据的约束。 AIM 1将检验以下假设，即LTF的诱导和巩固动力学受PKA和ERK激酶级联反应的动力学和CREB调节转录内的反馈回路的控制。模拟将检查培训方案的功效，并预测优化学习的协议。 AIM 2将检验LTF和LTP具有分子机制和动力学的假设。 模拟将识别控制参数，这可能对应于增强学习和认知的药理控制点。模拟还将探索由于影响CREB活性的突变，例如Rubinstein-Taybi综合征。最后，这些模型将用于预测改善CREB相关的记忆缺陷的治疗方法，从而有助于恢复正常的可塑性，学习和记忆。 公共卫生相关性：学习和记忆对于人类认知至关重要，它们的干扰有助于多种脑部疾病，包括神经纤维瘤病，鲁宾斯坦 - 塔比综合症和棺材 - 洛里综合征。该项目将促进对基本记忆机制的理解，这将导致更好的学习范式，并有助于确定用于脑疾病的药理学治疗的分子靶标。