Novel role of mitotic kinesin KIF11 in structural plasticity and memory
有丝分裂驱动蛋白 KIF11 在结构可塑性和记忆中的新作用
基本信息
- 批准号:10607093
- 负责人:
- 金额:$ 6.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Alzheimer&aposs DiseaseArchitectureBehaviorBehavioral ParadigmBindingBinding ProteinsBiological AssayBrainCOX7A2L ProteinCellsDataDefectDendritesDendritic SpinesDevelopmentDiseaseDorsalDynein ATPaseElectrophysiology (science)EnsureExhibitsExtinction (Psychology)FaceFrequenciesGenesGlutamatesGrowthHealthHippocampus (Brain)HumanImageIntellectual functioning disabilityIntracellular TransportKinesinLearningLearning DisordersLymphedemaMediatingMediator of activation proteinMemoryMental RetardationMicrocephalyMicrotubule ProteinsMicrotubulesMitosisMitoticMorphologyMotorMusMutationNeurobiologyNeuronsOperative Surgical ProceduresPenetrancePhysiologicalProtein FamilyProteinsRNA InterferenceRegulationRoleSynapsesSynaptic TransmissionSynaptic VesiclesSynaptic plasticitySynaptophysinSyndromeTestingTrainingVertebral columnWorkautism spectrum disorderdensityexperimental studygain of functionin vivoinsightknock-downlong term memoryloss of functionmembermental functionnervous system disordernoveloverexpressionpleiotropismpolarized cellpreservationprotein functionsynaptic functiontherapeutic developmenttwo photon microscopy
项目摘要
Project Summary
Mitotic cells dynamically regulate microtubule (MT) architecture through the use of the MT motors: kinesin and
dynein. Intriguingly, many of the canonical mitotic kinesins are expressed in post-mitotic neurons. These kinesins
are thought to participate in repositioning MTs in neurons, yet their precise function and how they are regulated
in neurons are unknown. Notably, mutations in kinesin-5 result in disorders associated with intellectual disabilities
in humans, however, there is a lack of mechanistic understanding of why this occurs. Previously, the
Puthanveettil lab revealed that members of the kinesin family of proteins (KIFs) are physiologically regulated in
neurons and are required for long-term memory storage. Recent studies from the lab uncovered that KIF11
(Kinesin-5), acts as an inhibitory constraint on excitatory synaptic transmission in hippocampal neurons. RNAi-
mediated loss-of-function analysis of KIF11 resulted in increased mini excitatory post-synaptic currents
frequencies, increased dendritic branching, and increased synapse density. KIF11 is the only known
homotetrameric kinesin, with four, slow motor domains that face outward to bind interpolar MTs during mitosis,
and brake against other kinesins to ensure proper spindle formation. It is unknown how KIF11 mediates structural
changes in hippocampal neurons, and whether KIF11 has a role in long-term memory storage. My central
hypothesis is that KIF11 mediated regulation of MT dynamics is required for the activity-dependent structural
changes in dendritic spines and long-term memory. To test this, in Aim1 I will uncover the mechanism behind
how KIF11 regulates structural plasticity through examining activity-dependent changes in spine morphology
following glutamate uncaging in WT, KIF11 KD, and KIF11 overexpression neurons by two-photon microscopy
(2P) imaging while simultaneously visualizing MT dynamics via EB1. In Aim 2 I will test the effects of the loss of
function and gain of function of KIF11 in dorsal CA1 neurons in learning and memory behavior assays.
Completion of these aims will bring novel insights into the mechanism and regulation of KIF11 in structural
plasticity and memory. Moreover, these studies will significantly advance our understanding of mitotic kinesins
in post-mitotic neurons.
项目概要
有丝分裂细胞通过使用 MT 马达动态调节微管 (MT) 结构:驱动蛋白和
动力蛋白。有趣的是,许多典型的有丝分裂驱动蛋白在有丝分裂后神经元中表达。这些驱动蛋白
被认为参与神经元中 MT 的重新定位,但它们的精确功能及其调节方式
神经元中的情况未知。值得注意的是,驱动蛋白 5 的突变会导致与智力障碍相关的疾病
然而,在人类中,人们对为什么会发生这种情况缺乏机械性的理解。此前,
Puthanveettil 实验室揭示了驱动蛋白家族 (KIF) 的成员在生理学上受到调节
神经元,是长期记忆存储所必需的。实验室最近的研究发现 KIF11
(Kinesin-5),作为海马神经元兴奋性突触传递的抑制性约束。 RNAi-
KIF11 介导的功能丧失分析导致微小兴奋性突触后电流增加
频率、树突分支增加和突触密度增加。 KIF11 是唯一已知的
同四聚体驱动蛋白,具有四个慢速运动结构域,在有丝分裂期间面向外结合极间 MT,
并制动其他驱动蛋白以确保纺锤体的正确形成。目前尚不清楚 KIF11 如何介导结构
海马神经元的变化,以及 KIF11 是否在长期记忆存储中发挥作用。我的中央
假设 KIF11 介导的 MT 动力学调节是活性依赖的结构所必需的
树突棘和长期记忆的变化。为了测试这一点,在 Aim1 中我将揭示背后的机制
KIF11 如何通过检查脊柱形态的活动依赖性变化来调节结构可塑性
通过双光子显微镜观察 WT、KIF11 KD 和 KIF11 过表达神经元中谷氨酸解笼锁后的情况
(2P) 成像,同时通过 EB1 可视化 MT 动态。在目标 2 中,我将测试损失的影响
KIF11 在学习和记忆行为测定中背侧 CA1 神经元的功能和功能获得。
这些目标的完成将为KIF11的结构机制和调控带来新的见解。
可塑性和记忆力。此外,这些研究将显着增进我们对有丝分裂驱动蛋白的理解
在有丝分裂后神经元中。
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)
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Jenna Lynne Wingfield其他文献
Jenna Lynne Wingfield的其他文献
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{{ truncateString('Jenna Lynne Wingfield', 18)}}的其他基金
Novel role of mitotic kinesin KIF11 in structural plasticity and memory
有丝分裂驱动蛋白 KIF11 在结构可塑性和记忆中的新作用
- 批准号:
10693878 - 财政年份:2022
- 资助金额:
$ 6.76万 - 项目类别:
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