MicroRNA101 and the Termination of Early Phase Neural Development
MicroRNA101 与早期神经发育的终止
基本信息
- 批准号:8914061
- 负责人:
- 金额:$ 19.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-01 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:AMPA ReceptorsAccountingAcuteAddressAdultAmyloidAutomobile DrivingBiological Neural NetworksBrainCalciumChloride IonChloridesComplexDevelopmentEpilepsyEventFailureFrequenciesFutureGoalsHealthImageIndividualInterventionInvestigationLifeMediatingMessenger RNAMicroRNAsN-Methyl-D-Aspartate ReceptorsNervous system structureNeuronal DifferentiationNeuronsOutcomePathway interactionsPhasePlayPopulationPoriferaProcessProteinsRegulationRegulatory PathwayReportingRoleScheduleShapesSignal TransductionSiteSliceSynapsesSynaptic plasticitySystemTestingTherapeuticTimeWorkcohortgamma-Aminobutyric Acidin vivoinhibitor/antagonistinsightinterestnervous system developmentnervous system disorderneurodevelopmentneuronal growthpatch clamppostnatalpreventregenerativesynaptogenesistransmission process
项目摘要
DESCRIPTION (provided by applicant): The developing nervous system undergoes a major transition in early postnatal life when it shifts from a period of exuberant synapse formation to a
subsequent period of synaptic pruning and network consolidation. Synaptic numbers approach a maximum during this time, the rules governing synaptic plasticity change, AMPA and NMDA receptor compositions are altered, and GABAergic signaling shifts from being depolarizing/excitatory to hyperpolarizing/inhibitory, in addition to other changes. Mechanisms driving this profound transition are poorly understood at best. Interesting candidates for doing so
are microRNAs (miRs) because they can target many different mRNAs at the same time for blockade or destruction, thereby producing a "regulatory hub" to coordinate complex changes across large systems. Our preliminary evidence indicates that miR-101 is an attractive candidate for executing this transition. It is abundant, increases substantially at the relevant time, and remains high in the adult. Using antagonists to block miR-101 function in vivo reveals significant aberrations: substantial increases are seen in spontaneous synchronized activity across neuronal populations and is accompanied by increases in synaptic number and excitatory synaptic input to neurons. Blocking miR-101 also appears to delay maturation of GABAergic signaling, enabling it to be depolarizing at later times. Importantly, our preliminary results using target site blockers to protect specific mRNAs suggest that miR-101 achieves its effects by acting on multiple targets. One is likely to be NKCC1, the chloride transporter responsible for GABA being depolarizing. But other miR-101 targets appear to be important as well, suggesting that terminating the depolarizing phase of GABAergic signaling is not by itself sufficient to account for all the major changes comprising the developmental transition. We will test the role of miR-101 in mediating the transition in nervous system development by using antagonists, sponges, and target site blockers to prevent its action in vivo while assessing the consequences for synaptic activity and network function. Calcium fluors in acute slices will report the frequency and extent of spontaneous coordinated activity across neuronal populations, as well as total activity and numbers of participating neurons. Patch-clamp recording will reveal type and amount of synaptic activity while immunostaining will quantify synapses. By selecting individual miR-101 targets for protection, it will be possible to dissect th contributions of different pathways to the transition and to evaluate the consequences of defective regulation. This will provide new insight into mechanisms driving the transition, reveal the role of miR-101 in particular, and likely have biomedical relevance by revealing the vulnerability of the system to individual regulatory pathways being compromised, producing, for example, greater propensity for epileptic seizure-like events.
描述(由申请人提供):发育中的神经系统在出生后的早期经历了一个主要的转变,当时它从旺盛的突触形成期转变为
随后突触修剪和网络巩固时期。在此期间,突触数量接近最大值,控制突触可塑性的规则发生变化,AMPA和NMDA受体组成发生变化,GABA能信号从去极化/兴奋转变为超极化/抑制,以及其他变化。推动这一深刻转变的机制充其量也只是知之甚少。有趣的候选人这样做
是微小RNA(miR),因为它们可以同时靶向许多不同的mRNA进行阻断或破坏,从而产生一个“调节中心”来协调大型系统中的复杂变化。我们的初步证据表明,miR-101是执行这种转变的有吸引力的候选者。它是丰富的,在相关的时间大幅增加,并保持在成人高。使用拮抗剂阻断体内miR-101功能揭示了显著的畸变:在神经元群体中观察到自发同步活动的显著增加,并伴随着突触数量和神经元兴奋性突触输入的增加。阻断miR-101似乎也延迟了GABA能信号传导的成熟,使其能够在稍后时间去极化。重要的是,我们使用靶点阻断剂保护特定mRNA的初步结果表明,miR-101通过作用于多个靶点来实现其作用。一个可能是NKCC 1,负责GABA去极化的氯转运蛋白。但其他miR-101靶点似乎也很重要,这表明终止GABA能信号的去极化阶段本身不足以解释发育过渡中的所有主要变化。我们将测试miR-101在神经系统发育中介导的过渡中的作用,通过使用拮抗剂,海绵和靶点阻断剂来防止其在体内的作用,同时评估突触活性和网络功能的后果。急性切片中的钙荧光剂将报告神经元群体之间自发协调活动的频率和程度,以及参与神经元的总活动和数量。膜片钳记录将揭示突触活动的类型和数量,而免疫染色将量化突触。通过选择单个miR-101保护靶点,将有可能分析不同途径对过渡的贡献,并评估缺陷调控的后果。这将为驱动这种转变的机制提供新的见解,特别是揭示miR-101的作用,并可能通过揭示系统对个体调控途径的脆弱性而具有生物医学相关性,例如,产生更大的癫痫样事件倾向。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
MicroRNA-101 Regulates Multiple Developmental Programs to Constrain Excitation in Adult Neural Networks.
- DOI:10.1016/j.neuron.2016.11.017
- 发表时间:2016-12-21
- 期刊:
- 影响因子:16.2
- 作者:Lippi G;Fernandes CC;Ewell LA;John D;Romoli B;Curia G;Taylor SR;Frady EP;Jensen AB;Liu JC;Chaabane MM;Belal C;Nathanson JL;Zoli M;Leutgeb JK;Biagini G;Yeo GW;Berg DK
- 通讯作者:Berg DK
{{
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 }}
Darwin K BERG其他文献
Darwin K BERG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('Darwin K BERG', 18)}}的其他基金
Long-Lasting Changes in Neural Networks Induced by Early Exposure to Nicotine
早期接触尼古丁引起的神经网络的长期变化
- 批准号:
8891987 - 财政年份:2015
- 资助金额:
$ 19.38万 - 项目类别:
MicroRNA101 and the Termination of Early Phase Neural Development
MicroRNA101 与早期神经发育的终止
- 批准号:
8823230 - 财政年份:2014
- 资助金额:
$ 19.38万 - 项目类别:
Revealing the connectivity and functionality of brain stem circuits
揭示脑干回路的连接性和功能
- 批准号:
8827174 - 财政年份:2014
- 资助金额:
$ 19.38万 - 项目类别:
Impact of Nicotinic Signaling through Astrocytes on Glutamate Synapse Formation
通过星形胶质细胞的烟碱信号传导对谷氨酸突触形成的影响
- 批准号:
8473843 - 财政年份:2012
- 资助金额:
$ 19.38万 - 项目类别:
Impact of Nicotinic Signaling through Astrocytes on Glutamate Synapse Formation
通过星形胶质细胞的烟碱信号传导对谷氨酸突触形成的影响
- 批准号:
8359365 - 财政年份:2012
- 资助金额:
$ 19.38万 - 项目类别:
CELLULAR & MOLECULAR NEUROBIOLOGY: SYNAPSE FORMATION & MODULATION
蜂窝网络
- 批准号:
7722311 - 财政年份:2008
- 资助金额:
$ 19.38万 - 项目类别:
CELLULAR & MOLECULAR NEUROBIOLOGY: SYNAPSE FORMATION & MODULATION
蜂窝网络
- 批准号:
7601658 - 财政年份:2007
- 资助金额:
$ 19.38万 - 项目类别:
CELLULAR & MOLECULAR NEUROBIOLOGY: SYNAPSE FORMATION & MODULATION
蜂窝网络
- 批准号:
7182034 - 财政年份:2005
- 资助金额:
$ 19.38万 - 项目类别:
CELLULAR & MOLECULAR NEUROBIOLOGY: SYNAPSE FORMATION & MODULATION
蜂窝网络
- 批准号:
6975459 - 财政年份:2004
- 资助金额:
$ 19.38万 - 项目类别:
Beta-Amyloid Blockade of Hippocampal Nicotinic Alpha7-R*
海马烟碱 Alpha7-R* 的 β-淀粉样蛋白阻断
- 批准号:
6333445 - 财政年份:2001
- 资助金额:
$ 19.38万 - 项目类别:
相似海外基金
Unraveling the Dynamics of International Accounting: Exploring the Impact of IFRS Adoption on Firms' Financial Reporting and Business Strategies
揭示国际会计的动态:探索采用 IFRS 对公司财务报告和业务战略的影响
- 批准号:
24K16488 - 财政年份:2024
- 资助金额:
$ 19.38万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Mighty Accounting - Accountancy Automation for 1-person limited companies.
Mighty Accounting - 1 人有限公司的会计自动化。
- 批准号:
10100360 - 财政年份:2024
- 资助金额:
$ 19.38万 - 项目类别:
Collaborative R&D
Accounting for the Fall of Silver? Western exchange banking practice, 1870-1910
白银下跌的原因是什么?
- 批准号:
24K04974 - 财政年份:2024
- 资助金额:
$ 19.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A New Direction in Accounting Education for IT Human Resources
IT人力资源会计教育的新方向
- 批准号:
23K01686 - 财政年份:2023
- 资助金额:
$ 19.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
An empirical and theoretical study of the double-accounting system in 19th-century American and British public utility companies
19世纪美国和英国公用事业公司双重会计制度的实证和理论研究
- 批准号:
23K01692 - 财政年份:2023
- 资助金额:
$ 19.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
An Empirical Analysis of the Value Effect: An Accounting Viewpoint
价值效应的实证分析:会计观点
- 批准号:
23K01695 - 财政年份:2023
- 资助金额:
$ 19.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Accounting model for improving performance on the health and productivity management
提高健康和生产力管理绩效的会计模型
- 批准号:
23K01713 - 财政年份:2023
- 资助金额:
$ 19.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
CPS: Medium: Making Every Drop Count: Accounting for Spatiotemporal Variability of Water Needs for Proactive Scheduling of Variable Rate Irrigation Systems
CPS:中:让每一滴水都发挥作用:考虑用水需求的时空变化,主动调度可变速率灌溉系统
- 批准号:
2312319 - 财政年份:2023
- 资助金额:
$ 19.38万 - 项目类别:
Standard Grant
New Role of Not-for-Profit Entities and Their Accounting Standards to Be Unified
非营利实体的新角色及其会计准则将统一
- 批准号:
23K01715 - 财政年份:2023
- 资助金额:
$ 19.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
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:
$ 19.38万 - 项目类别: