Activity dependent mechanisms of olfactory system development
嗅觉系统发育的活动依赖机制
基本信息
- 批准号:8677588
- 负责人:
- 金额:$ 11.95万
- 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:2012-07-01 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAfferent NeuronsAnimalsAreaAxonBehaviorBindingBiological AssayBrainCardiacCyclic AMPCyclic NucleotidesCytoskeletonDevelopmentElectroporationEmbryoEpilepsyEventFilopodiaFutureGTP-Binding ProteinsGoalsGrowthGrowth ConesImageImageryIn VitroInvestigationIon ChannelKineticsLocationMeasuresMediatingMembrane PotentialsMesenchymeMusNasal cavityNeuraxisNeuritesOdorant ReceptorsOdorsOlfactory EpitheliumPeripheralPhasePlasmidsProcessRegulationReportingResearchRoleSignal TransductionSinus BradycardiaSorting - Cell MovementStimulusSyndromeSystemSystems DevelopmentTechniquesTestingUp-Regulationage relatedaxon growthchannel blockerscritical periodcyclic-nucleotide gated ion channelsdesignimmunocytochemistryin uteroin vivointerestneuronal cell bodynovel strategiesolfactory bulbpainful neuropathypostnatalresearch studysmall hairpin RNA
项目摘要
DESCRIPTION (provided by applicant): During development, the olfactory sensory neuron (OSN) axons navigate through the mesenchyme, coalesce with other axons expressing the same odorant receptor, and converge into a glomerulus in a topographically defined region of the olfactory bulb (OB). Although considerable effort has been made, the mechanisms regulating these events are not well understood. My long- term goal is to understand the mechanisms mediating this progression. Currently I am interested in the role that functional activity has in these events. This application focuses on the contribution of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity to olfactory development. The HCN channel current Ih was first characterized in cardiac pacemaking activity; the channels are found extensively in the central nervous system. HCN channels are gated by cAMP, which can affect channel kinetics depending on which of the four HCN subunits (HCN1-4) are present. The cyclic nucleotide binding domain of HCN channels make them good candidates for affecting the cAMP activity recently implicated in olfactory system development (Imai et al., 2006, Zou et al., 2007, Chesler et al., 2007).
The following aims are designed to determine the role of HCN channels in OSN axon outgrowth, growth cone activity, coalescence and glomerular formation. We previously showed an upregulation of the HCN2 subunit during development (Mobley et al., 2010). Specific Aim 1 examines the mechanisms underlying the role of HCN2, which is strongly modulated by cAMP, in development. I will employ in utero electroporation of the olfactory epithelium to introduce a plasmid expressing GFP and HCN2 shRNA targeting OSNs. This original technique adapted to the nasal cavity will enable visualization of OSN axon behavior in vivo and may have a lasting influence on future studies of OSN dynamics. Specific Aim 2 examines the role of HCN channels and membrane potential in growth cone lamellipodia formation. Guidance signal-induced cAMP signaling is important for OSN axon growth cone targeting and coalescence. Elsewhere in brain cyclic nucleotide signaling is implicated in growth cone dynamics, though the role of HCN channels has not been explored (Ming et al., 1997; Maritan et al., 2009; Murray et al., 2009). Thus, our analyses of HCN mediated growth cone dynamics in OSNs would not only impact olfactory system development but on developmental mechanisms throughout the brain. Specific Aim 2 will challenge OSNs in vitro with membrane potential changes and HCN channel blockers to measure changes in growth cone lamellipodia and filopodia. Demonstrating a role for HCN channels in growth cone dynamics would impact a much larger field than olfactory research and provide new avenues for investigating activity dependent mechanisms of olfactory system development.
The results of these studies may provide mechanisms for OSN axon targeting during development such as age-dependent subunit regulation and membrane potential-induced growth cone dynamics. The experiments proposed here may have broad implications for Ih channelopathies including sinus bradycardia, epilepsy, and peripheral neuropathic pain.
描述(由申请人提供):在发育过程中,嗅觉感觉神经元(OSN)轴突在间质中导航,与其他表达相同odor剂受体的轴突合并,并在嗅觉块(OB)的地形定义的区域中收敛成肾小球。尽管已经付出了巨大的努力,但是调节这些事件的机制尚未得到充分理解。我的长期目标是了解介导这种进展的机制。目前,我对功能活动在这些事件中的作用感兴趣。该应用重点是超极化激活的环状核苷酸门控(HCN)通道活性对嗅觉发育的贡献。 HCN通道电流IH首先是在心脏起搏活动中的特征。通道在中枢神经系统中广泛发现。 HCN通道由CAMP门控,这可能会影响通道动力学,这取决于存在四个HCN亚基(HCN1-4)中的哪个。 HCN通道的环状核苷酸结合结构域使其成为影响最近与嗅觉系统开发有关的营地活动的良好候选者(Imai等,2006; Zou等,2007; Chesler等,Chesler等,2007)。
以下目的旨在确定HCN通道在OSN轴突生长,生长锥活性,合并和肾小球形成中的作用。我们先前在开发过程中表现出HCN2亚基的上调(Mobley等,2010)。具体目标1研究了HCN2作用的基础机制,HCN2在开发中受到了强烈的调节。我将利用嗅觉上皮的子宫电穿孔来引入表达GFP和HCN2 shRNA靶向OSN的质粒。适合鼻腔的原始技术将使体内OSN轴突行为可视化,并可能对OSN动力学的未来研究产生持久影响。具体目标2研究了HCN通道和膜潜力在生长锥层形成中的作用。引导信号诱导的cAMP信号对于OSN轴突生长锥靶向和合并很重要。尽管尚未探索HCN通道的作用,但在脑周期性核苷酸的其他地方与生长锥动力学有关(Ming等,1997; Maritan等,2009; Murray等,2009)。因此,我们对HCN介导的OSN中介导的生长锥动力学的分析不仅会影响嗅觉系统的发展,还会影响整个大脑的发育机制。特定的AIM 2将在体外挑战OSN,并随膜电位变化和HCN通道阻滞剂来衡量生长锥层片和丝状虫的变化。证明HCN通道在生长锥动力学中的作用将影响比嗅觉研究更大的领域,并为研究嗅觉系统开发的活动依赖机制提供了新的途径。
这些研究的结果可能会为OSN轴突靶向开发提供机制,例如年龄依赖性亚基调控和膜电位诱导的生长锥体动力学。这里提出的实验可能对包括窦性心动过缓,癫痫和周围神经性疼痛在内的IH通道病具有广泛的影响。
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 }}
Arie Sitthichai Mobley其他文献
Arie Sitthichai Mobley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('Arie Sitthichai Mobley', 18)}}的其他基金
Activity dependent mechanisms of olfactory system development
嗅觉系统发育的活动依赖机制
- 批准号:
8492059 - 财政年份:2012
- 资助金额:
$ 11.95万 - 项目类别:
Activity dependent mechanisms of olfactory system development
嗅觉系统发育的活动依赖机制
- 批准号:
8368090 - 财政年份:2012
- 资助金额:
$ 11.95万 - 项目类别:
Mechanisms of embryonic olfactory sensory neuron axon targeting
胚胎嗅觉感觉神经元轴突靶向机制
- 批准号:
7804230 - 财政年份:2009
- 资助金额:
$ 11.95万 - 项目类别:
Mechanisms of embryonic olfactory sensory neuron axon targeting
胚胎嗅觉感觉神经元轴突靶向机制
- 批准号:
7933956 - 财政年份:2009
- 资助金额:
$ 11.95万 - 项目类别:
相似国自然基金
面向类脑智能感知的编码运算一体化柔性电子传入神经元的研究
- 批准号:
- 批准年份:2021
- 资助金额:60 万元
- 项目类别:面上项目
面向类脑智能感知的编码运算一体化柔性电子传入神经元的研究
- 批准号:62174130
- 批准年份:2021
- 资助金额:60.00 万元
- 项目类别:面上项目
不同刺灸法激活的穴位传入神经元及时间-空间反应特性
- 批准号:81973967
- 批准年份:2019
- 资助金额:55 万元
- 项目类别:面上项目
有髓传入神经纤维相应DRG神经元中Cav3.2通道N-糖基化在DPN触诱发痛发生发展中的作用机制研究
- 批准号:81801219
- 批准年份:2018
- 资助金额:21.0 万元
- 项目类别:青年科学基金项目
通过内皮素-1探索初级传入神经元感受疼痛或搔痒的细胞机制
- 批准号:81171040
- 批准年份:2011
- 资助金额:55.0 万元
- 项目类别:面上项目
相似海外基金
The Role of Astrocyte Elevated Gene-1 (AEG-1), A Novel Multifunctional Protein, In Chemotherapy-Induced Peripheral Neuropathy
星形胶质细胞升高基因 1 (AEG-1)(一种新型多功能蛋白)在化疗引起的周围神经病变中的作用
- 批准号:
10679708 - 财政年份:2023
- 资助金额:
$ 11.95万 - 项目类别:
The Injectrode- An injectable, easily removable electrode as a trial lead for baroreceptor activation therapy to treat hypertension and heart failure
Injectrode——一种可注射、易于拆卸的电极,作为压力感受器激活疗法的试验引线,以治疗高血压和心力衰竭
- 批准号:
10697600 - 财政年份:2023
- 资助金额:
$ 11.95万 - 项目类别:
Selective actin remodeling of sensory neurons for acute pain management
感觉神经元的选择性肌动蛋白重塑用于急性疼痛管理
- 批准号:
10603436 - 财政年份:2023
- 资助金额:
$ 11.95万 - 项目类别:
Mitochondrial regulation of nociceptor function
伤害感受器功能的线粒体调节
- 批准号:
10644865 - 财政年份:2023
- 资助金额:
$ 11.95万 - 项目类别:
Neuroimmune interactions for laryngeal sensorimotor neuropathy in postviral influenza infection
病毒性流感感染后喉部感觉运动神经病变的神经免疫相互作用
- 批准号:
10827254 - 财政年份:2023
- 资助金额:
$ 11.95万 - 项目类别: