DAPK1 regulation and involvement in LTD
DAPK1 的调控和参与 LTD
基本信息
- 批准号:9033016
- 负责人:
- 金额:$ 3.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-03-01 至 2018-02-28
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectApoptosisAttenuatedAutophagocytosisBindingBiochemicalBiochemistryC-terminalCalcineurinCalmodulinCell DeathCellsCessation of lifeChemosensitizationClinicalDAP kinaseDataElectrophysiology (science)Excitatory SynapseGeneticGlutamate ReceptorGlutamatesHippocampus (Brain)In VitroInjuryKnock-in MouseKnockout MiceKnowledgeLifeLocationLong-Term DepressionLong-Term PotentiationMediatingMediator of activation proteinModelingMusMutant Strains MiceN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNeuronal InjuryNeuronsPathway interactionsPhosphoric Monoester HydrolasesPhosphorylationPhosphorylation SitePhysiologicalPlayProtein Serine/Threonine PhosphataseProtein-Serine-Threonine KinasesRegulationRoleSerineSignal PathwaySignal TransductionSliceSpecificityStimulusStrokeSynapsesSynaptic plasticityTailTestingTraumatic Brain Injuryclinically relevantdesigndrug discoveryexcitotoxicityinhibitor/antagonistinsightmutantnervous system disorderneuron lossneurotoxicnovelnovel therapeuticspreventprotein protein interactionpublic health relevanceresearch studysynaptic function
项目摘要
DESCRIPTION (provided by applicant): Death associated protein kinase 1 (DAPK1) mediates cellular death after neuronal injury. An essential function of DAPK1 in acute neuronal death is its
binding to the GluN2B subunit of the N-methyl-D-aspartate type glutamate receptor (NMDAR) and phosphorylation of serine 1303 of GluN2B. Phosphorylation of this site results in increased NMDAR conductance and neurotoxic increases in intracellular Ca2+ influx. Importantly, disrupting DAPK1 activity or DAPK1/GluN2B binding in several models of neuronal injury results in attenuated cell death. Despite this, the regulation of DAPK1 binding to GluN2B remains completely unexplored. Pathological activation of DAPK1 occurs in an NMDAR and calcineurin (CaN) dependent manner. The NMDAR also plays a particularly important role in synaptic plasticity, and its activation is required for synaptic long-term potentiation (LTP) as well as som forms of long-term depression (LTD) in the hippocampus. Additionally, LTD also requires CaN activation, suggesting that DAPK1 may also be activated during physiological synaptic plasticity. Aim 1: To determine the regulatory mechanisms of DAPK1/GluN2B binding in vitro and in cells. Aim1.1: To test the hypothesis that DAPK1 binding to GluN2B is regulated by Ca2+/calmodulin and phosphorylation state. The specific regulation of DAPK1 binding to GluN2B will be examined in vitro and in cells using DAPK1 mutants that mimic different phosphorylation and activation states. Aim 1.2: To test the hypothesis that DAPK1 translocation to excitatory synapses is induced by LTD and excitotoxicity, but not LTP. DAPK1 targeting to excitatory synapses will be examined in dissociated hippocampal neurons during stimuli eliciting LTD, LTP, or excitotoxicity. Aim 2: To determine the role of DAPK1 in synaptic plasticity. Aim 2.1: To test the hypothesis that DAPK1 is activated in a CaN dependent manner during LTD. Slice biochemical studies will be used to investigate if DAPK1 is activated during LTD, the activating phosphatase(s), and whether a downstream effector of DAPK1 is affected. Aim 2.2: To test the hypothesis that DAPK1 activity and the DAPK1/GluN2B interaction are necessary for the induction of LTD. The functional effects of DAPK1 and the DAPK1/GluN2B interaction will be investigated in mouse hippocampal slices using electrophysiological recordings and slice biochemistry. A combination of pharmacological DAPK1 inhibitors and two mutant mice will be used to examine the function of DAPK1 in synaptic plasticity. The results of this proposal will establish the regulatory mechanisms underlying the DAPK1/GluN2B interaction that promotes neuronal cell death after glutamate insults during stroke or traumatic brain injury. Additionally, novel role for DAPK1 in synaptic plasticity will be examined.
描述(申请人提供):死亡相关蛋白激酶1(DAPK1)介导神经元损伤后的细胞死亡。DAPK1在急性神经元死亡中的一个基本功能是其
与N-甲基-D-天冬氨酸型谷氨酸受体(NMDAR)的GluN2B亚基结合,以及GluN2B的丝氨酸1303的磷酸化。该位点的磷酸化导致NMDAR电导增加和细胞内钙离子内流的神经毒性增加。重要的是,在几种神经元损伤模型中,破坏DAPK1活性或DAPK1/GluN2B结合会导致减弱的细胞死亡。尽管如此,DAPK1与GluN2B结合的调控仍然完全未知。DAPK1的病理性激活依赖于NMDAR和钙调神经磷酸酶(CaN)。NMDAR在突触可塑性中也起着特别重要的作用,它的激活是突触长时程增强(LTP)和某些形式的长时程增强(LTD)在海马区所必需的。此外,LTD还需要激活CaN,这表明DAPK1在生理性突触可塑性过程中也可能被激活。目的1:探讨DAPK1/GluN2B在体外和细胞内结合的调控机制。目的:验证DAPK1与GluN2B结合受钙/钙调蛋白和磷酸化状态调节的假说。DAPK1与GluN2B结合的特异性调节将在体外和使用模拟不同磷酸化和激活状态的DAPK1突变体在细胞中进行检测。目的1.2:验证LTP和LTP诱导DAPK1易位至兴奋性突触的假说。针对兴奋性突触的DAPK1将在刺激诱发LTD、LTP或兴奋性毒性时在分离的海马神经元中进行检测。目的:探讨DAPK1在突触可塑性中的作用。目的2.1:验证DAPK1在LTD期间以CaN依赖的方式被激活的假说。切片生化研究将用于研究DAPK1在LTD期间是否被激活,激活的磷酸酶(S),以及DAPK1的下游效应因子是否受到影响。目的2.2:验证DAPK1活性和DAPK1/GluN2B相互作用是LTD诱导所必需的假说。DAPK1的功能效应和DAPK1/GluN2B的相互作用将在小鼠海马片上利用电生理记录和切片生物化学进行研究。药物DAPK1抑制剂和两只突变小鼠的组合将被用来检测DAPK1在突触可塑性中的功能。该提案的结果将建立DAPK1/GluN2B相互作用的调节机制,该相互作用促进中风或创伤性脑损伤期间谷氨酸损伤后神经细胞的死亡。此外,还将研究DAPK1在突触可塑性中的新作用。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Dayton Joshua Goodell其他文献
Dayton Joshua Goodell的其他文献
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{{ truncateString('Dayton Joshua Goodell', 18)}}的其他基金
NRAP-1 control of NMDA receptor-mediated synaptic transmission
NRAP-1 控制 NMDA 受体介导的突触传递
- 批准号:
9810931 - 财政年份:2019
- 资助金额:
$ 3.08万 - 项目类别:
NRAP-1 control of NMDA receptor-mediated synaptic transmission
NRAP-1 控制 NMDA 受体介导的突触传递
- 批准号:
9977001 - 财政年份:2019
- 资助金额:
$ 3.08万 - 项目类别:
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