CRCNS: PKMzeta-Dependent Protein Synthesis Maintains Synaptic Plasticity
CRCNS:PKMzeta 依赖性蛋白质合成维持突触可塑性
基本信息
- 批准号:8840208
- 负责人:
- 金额:$ 28.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-07-15 至 2016-04-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAgeBackBehavioralBindingBiochemicalBiological SciencesBiologyBrainCalciumCalmodulinChemosensitizationClinicalCollaborationsCommunitiesComputational BiologyComputer SimulationDependenceDiffuseDiffusionDisadvantagedDrug abuseEducationFeedbackGoalsGrantHigh School StudentHippocampus (Brain)HourHousingHumanIn VitroInformation StorageInstructionKineticsKnowledgeLearningLifeLong-Term PotentiationMaintenanceMediatingMemoryMental disordersMentorsMethodologyModelingMolecularMolecular ConformationNeurosciencesNew YorkPathway interactionsPharmaceutical PreparationsPhasePhosphorylationPhosphotransferasesPlayPost-Traumatic Stress DisordersPropertyProtein BiosynthesisProtein IsoformsProtein KinaseProtein Kinase CProtein Synthesis InhibitorsProteinsQualifyingRecording of previous eventsRegulationResearchRiceRoleScienceScientistSiteSliceSolidSolutionsStudentsSynapsesSynaptic TransmissionSynaptic plasticitySystemTechniquesTestingTheoretical modelTimeToxic effectTrainingTranslationsWorkYouthabstractingaddictionbasebiophysical modeldrug rewarddrug seeking behaviorexperiencein vivoinhibitor/antagonistinterestlink proteinlong term memorymathematical modelnervous system disorderneuronal circuitrynoveloutreachpainful neuropathyprogramsprotein degradationresearch studyresponsesimulationtheories
项目摘要
DESCRIPTION (provided by applicant): We all have memories that date back to our youth; we remember the house we lived in at age 4; we remember a favorite schoolteacher. The mechanism for storing these memories is believed to be the long-term plasticity of synaptic connections within specific neuronal circuits. However, this putative cellular basis of memory relies on proteins that typically have lifetimes far shorter than the memory. Here exactly lies a fundamental problem of long-term memory and synaptic plasticity: How can memories be stored for a human lifetime on the basis of proteins that are continuously degrading? Recently, it was shown that the brain-specific PKC isoform, protein kinase Mζ(PKMζ), plays a unique role in maintaining both late long-term potentiation (L-LTP) of synapses and long-term memory. This crucial observation, however, does not explain how PKMζcan overcome the natural degrading effect of protein turnover and diffusion. The central hypothesis of this proposal is that PKMζ, through its control of its own synthesis, can form a bi-stable system, which can account for the maintenance of synapse specific long-term plasticity and memory. Here we propose to mathematically formulate this hypothesis within a biophysical model, and to analyze this model so as to propose testable experimental predictions. We then will directly test these predictions on PKMζ-mediated persistent synaptic potentiation, using novel techniques tailored for testing the theory. Intellectual Merit: The finding that PKMζ is both necessary and sufficient for the maintenance of synaptic plasticity and long-term memory has fundamentally changed the field of learning and memory, but much needs to be learned about the mechanisms that can actually accomplish the persistence of long-term plasticity and memory. This proposal addresses these questions using a combined theoretical and experimental approach. Such a theory in which bi-stability depends on regulation of translation is novel not only for neuroscience but also for biology in general. Our collaboration is uniquely qualified to carry out the proposed work because the Shouval lab has ample experience in modeling synaptic plasticity in collaboration with experimental groups, and the Sacktor lab has pioneered the science of PKM??and has ample experience with the proposed techniques. The experimental techniques include two new methodologies necessary for testing the predictions. First, we propose to test the model's predictions on protein translation in L-LTP, not by general protein synthesis inhibitors that may have issues of toxicity and indirect effects, but by use of antisense oligodeoxynucleotides directed to the translation start site of PKMζmRNA to specifically block PKMζ synthesis in induction and maintenance. Second, because PKMζ-mediated potentiation is both highly stable and yet rapidly reversible, we will use a fast-flow hippocampal slice chamber optimized for the study of the maintenance of L-LTP to test key predictions of the model. The proposed stochastic simulations of translation-dependent bi-stability are also novel in computational biology. Broader Impact: As the first demonstrated molecular mechanism of experience-dependent, long-term information storage in the brain, PKMζ has significant clinical implications, and within the last year has been shown to contribute to in the biology of a variety of neurological and psychiatric diseases, including post-traumatic stress disorder, central neuropathic pain, and drug abuse. In order to assist the rapidly growing interest in PKMζ in many labs, we will make our model accessible to the larger community, allowing for other scientists to test, modify, and incorporate their findings into the model, thus accelerating the pace of scientific discovery. Because an important goal for NSF is to integrate research and education, we will train a diverse pool of students. Our labs already train undergraduates, the Shouval lab takes undergraduates each summer through an REU program (PI S. Cox, Rice), and a UT system grant (PI H. Shouval), and local undergraduates throughout the year, and the Sacktor lab has had a long history of mentoring local disadvantaged high school students (e.g., through the Intel program). Both labs are dedicated to public outreach; for example, an article on PKMζ and memory was on the front page of The New York Times. We are eager to extend this type of outreach to the domain of the interaction between theory and experiment in biological sciences.
描述(由申请人提供):我们都有可以追溯到年轻时的记忆;我们记得我们四岁时住过的房子;我们记得最喜欢的老师。存储这些记忆的机制被认为是长期可塑性。然而,这种假定的记忆细胞基础依赖于寿命通常比记忆短得多的蛋白质,这正是长期记忆和突触可塑性的基本问题:如何存储记忆。最近,研究表明,大脑特有的 PKC 异构体,蛋白激酶 M z (PKM z),在维持晚期长时程增强 (L-LTP) 方面发挥着独特的作用。然而,这一重要的观察并不能解释 PKM z 如何克服蛋白质周转和扩散的自然降解效应。它对其自身合成的控制,可以形成一个双稳态系统,可以解释突触特异性长期可塑性和记忆的维持。在这里,我们建议在生物物理模型中以数学方式表述这一假设,并分析该模型。然后,我们将使用为测试该理论而定制的新技术,直接测试这些关于 PKM 介导的持续突触增强的预测:发现 PKM 是必要且充分的。维持突触可塑性和长期记忆的研究从根本上改变了学习和记忆领域,但对于真正能够实现长期可塑性和记忆持久性的机制,我们还需要了解很多。该提案解决了这些问题。这种双稳定性依赖于翻译调节的理论不仅对于神经科学而且对于整个生物学来说都是新颖的,因为舒瓦尔实验室有足够的资源来开展这项工作。突触可塑性建模经验Sacktor 实验室与实验小组合作,开创了 PKM 科学,并且在所提出的技术方面拥有丰富的经验。首先,我们建议测试模型的预测。 L-LTP中的蛋白质翻译,不是通过可能存在毒性和间接影响问题的一般蛋白质合成抑制剂,而是通过使用针对PKM zmRNA翻译起始位点的反义寡脱氧核苷酸来特异性阻断其次,由于 PKM 介导的增强作用高度稳定且可快速逆转,因此我们将使用针对 L-LTP 维持研究而优化的快速流动海马切片室来测试 L-LTP 维持的关键预测。所提出的翻译依赖性双稳定性的随机模拟在计算生物学中也是新颖的:作为第一个证明的大脑中经验依赖性长期信息存储的分子机制, PKM z 具有重要的临床意义,并且在去年已被证明有助于多种神经和精神疾病的生物学,包括创伤后应激障碍、中枢神经性疼痛和药物滥用。随着许多实验室对 PKM z 的兴趣日益浓厚,我们将使我们的模型可供更大的社区使用,允许其他科学家测试、修改并将他们的发现纳入模型中,从而加快科学发现的步伐,因为这是 NSF 的重要目标。就是要整合研究我们的实验室已经培养了本科生,Shouval 实验室每年夏天都会通过 REU 项目(PI S. Cox,Rice)和 UT 系统补助金(PI H. Shouval)招收本科生,萨克托实验室在指导当地弱势高中生方面有着悠久的历史(例如,通过英特尔计划),例如,一篇关于公共宣传的文章; PKM z 和记忆登上了《纽约时报》的头版,我们渴望将这种类型的推广扩展到生物科学理论与实验之间的相互作用领域。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
HAREL Zeev SHOUVAL其他文献
HAREL Zeev SHOUVAL的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('HAREL Zeev SHOUVAL', 18)}}的其他基金
CRCNS: PKMzeta-Dependent Protein Synthesis Maintains Synaptic Plasticity
CRCNS:PKMzeta 依赖性蛋白质合成维持突触可塑性
- 批准号:
8507210 - 财政年份:2012
- 资助金额:
$ 28.32万 - 项目类别:
CRCNS: PKMzeta-Dependent Protein Synthesis Maintains Synaptic Plasticity
CRCNS:PKMzeta 依赖性蛋白质合成维持突触可塑性
- 批准号:
9059060 - 财政年份:2012
- 资助金额:
$ 28.32万 - 项目类别:
CRCNS: PKMzeta-Dependent Protein Synthesis Maintains Synaptic Plasticity
CRCNS:PKMzeta 依赖性蛋白质合成维持突触可塑性
- 批准号:
8444766 - 财政年份:2012
- 资助金额:
$ 28.32万 - 项目类别:
CRCNS: PKMzeta-Dependent Protein Synthesis Maintains Synaptic Plasticity
CRCNS:PKMzeta 依赖性蛋白质合成维持突触可塑性
- 批准号:
8652969 - 财政年份:2012
- 资助金额:
$ 28.32万 - 项目类别:
An Integrated Approach to Synaptic Plasticity in the Hippocampus
海马突触可塑性的综合方法
- 批准号:
6995174 - 财政年份:2005
- 资助金额:
$ 28.32万 - 项目类别:
An Integrated Approach to Synaptic Plasticity in the Hippocampus
海马突触可塑性的综合方法
- 批准号:
7312744 - 财政年份:
- 资助金额:
$ 28.32万 - 项目类别:
An Integrated Approach to Synaptic Plasticity in the Hippocampus
海马突触可塑性的综合方法
- 批准号:
7463735 - 财政年份:
- 资助金额:
$ 28.32万 - 项目类别:
相似国自然基金
时空序列驱动的神经形态视觉目标识别算法研究
- 批准号:61906126
- 批准年份:2019
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
本体驱动的地址数据空间语义建模与地址匹配方法
- 批准号:41901325
- 批准年份:2019
- 资助金额:22.0 万元
- 项目类别:青年科学基金项目
大容量固态硬盘地址映射表优化设计与访存优化研究
- 批准号:61802133
- 批准年份:2018
- 资助金额:23.0 万元
- 项目类别:青年科学基金项目
针对内存攻击对象的内存安全防御技术研究
- 批准号:61802432
- 批准年份:2018
- 资助金额:25.0 万元
- 项目类别:青年科学基金项目
IP地址驱动的多径路由及流量传输控制研究
- 批准号:61872252
- 批准年份:2018
- 资助金额:64.0 万元
- 项目类别:面上项目
相似海外基金
An active learning framework for adaptive autism healthcare
适应性自闭症医疗保健的主动学习框架
- 批准号:
10716509 - 财政年份:2023
- 资助金额:
$ 28.32万 - 项目类别:
Mapping the Neurobiological Risks and Consequences of Alcohol Use in Adolescence and Across the Lifespan
绘制青春期和整个生命周期饮酒的神经生物学风险和后果
- 批准号:
10733406 - 财政年份:2023
- 资助金额:
$ 28.32万 - 项目类别:
Improving Age- and Cause-Specific Under-Five Mortality Rates (ACSU5MR) by Systematically Accounting Measurement Errors to Inform Child Survival Decision Making in Low Income Countries
通过系统地核算测量误差来改善特定年龄和特定原因的五岁以下死亡率 (ACSU5MR),为低收入国家的儿童生存决策提供信息
- 批准号:
10585388 - 财政年份:2023
- 资助金额:
$ 28.32万 - 项目类别:
The impact of bilingualism on cognitive reserve/resilience using socio-demographically and linguistically diverse populations
双语对社会人口和语言多样化人群的认知储备/弹性的影响
- 批准号:
10584245 - 财政年份:2023
- 资助金额:
$ 28.32万 - 项目类别:
Bayesian Statistical Learning for Robust and Generalizable Causal Inferences in Alzheimer Disease and Related Disorders Research
贝叶斯统计学习在阿尔茨海默病和相关疾病研究中进行稳健且可推广的因果推论
- 批准号:
10590913 - 财政年份:2023
- 资助金额:
$ 28.32万 - 项目类别: