Endogenous Ion Channel Activity Tracers to Monitor the Involvement of Kv2 Channels During Ischemic Attack
内源性离子通道活动示踪剂监测缺血性发作期间 Kv2 通道的参与情况
基本信息
- 批准号:9761043
- 负责人:
- 金额:$ 3.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-02 至 2022-04-01
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimalsApoptosisApoptoticBiochemical ProcessBrainCephalicCerebral ThrombosisComplexCritical ThinkingDendritesDependenceDevelopmentDiffuseDiffusionDrug TargetingElectrophysiology (science)EngineeringEventFluorescent ProbesGated Ion ChannelGenetic ModelsGenetic TechniquesHealthImageIndividualIon ChannelIon Channel GatingIschemiaIschemic StrokeKnowledgeLocationMeasuresMediatingMembraneMiddle Cerebral Artery OcclusionModelingMolecularMolecular ConformationMolecular ProbesMonitorMorphologyNeuronsPatternPharmacologyPhysiologicalPlayPotassiumPotassium ChannelProceduresPublic SpeakingRefractoryReportingResearchResolutionRoleSignal TransductionSliceSpecificityStressStrokeSumSystemTechniquesTechnologyTestingTimeTissuesTracerTrainingTransfectionWorkbaseexcitotoxicityexperimental studyfluorescence imaginghuman tissueimaging approachimprovedin vivoneuron lossneuronal cell bodyneuronal survivalneurotransmissionpreservationprotein activationrelating to nervous systemresponseskillsspatiotemporalspectrographtargeted treatmenttwo-photonvoltagevoltage clamp
项目摘要
Project Summary/Abstract
Endogenous Ion Channel Activity Tracers to Monitor the Involvement of Kv2 Channels During Ischemic Attack
Neuronal electrical signals are governed by the combined action of many ion channel subtypes.
Different sets of ion channels sum to create a remarkable diversity in neuronal electrical excitability. However,
due to technological limitations, dissecting the individual role of an ion channel subtype during a complex
physiological or pathophysiological event remains difficult. Consequently we have a limited understanding of
how the electrical dynamics of individual endogenous ion channel subtypes contribute to global signals,
especially in intact tissue or in live animals. Technology developed in Dr. Jon Sack’s lab offers an opportunity
to image the activity of ion channel subtypes throughout a complex tissue. Specifically, these
Kv2 Activity Tracers (KATs) report activation of endogenous neuronal potassium voltage-gated ion channels of
subtype 2. We have engineered these KATs for 2-photon imaging, and demonstrated that KATs can report
activation endogenous neuronal Kv2 ion channels in brain slices. I propose to measure activation of a specific
ion channel subtype in tissue slices and live animals under pathophysiological ischemic stress that mimics
stroke. In the brain, Kv2 ion channels are highly expressed in most, if not all neurons. Kv2 channels are
proposed to be crucial to suppress excitotoxic signaling events during many stresses, including ischemic
attack. Previous studies have suggested that Kv2 ion channels become very active during ischemia, suppress
electrical excitability, and provide neural protection from excitotoxic signaling. However, there has also been
evidence that excessive efflux of potassium through Kv2 channels during ischemia can trigger apoptotic
cascades leading to neuronal death. Both of these proposed roles assume a dramatic increase in the number
of active Kv2 channels, yet this has never been observed in real time in complex tissues. For my doctoral
studies I will probe a mechanism for mass activation, and image changes in Kv2 ion channel activity in models
of ischemic stroke. My results will improve our understanding of the molecular mechanisms leading to neuronal
cells death following stroke, and whether Kv2 channels are a potential drug target to increase neuronal survival
following stroke. Further, my research will be the first attempt at using fluorescent probes to measure
conformational change of specific ion channels in intact tissue and potentially transform the way protein
activation is studied in a physiological context. Throughout this project the sponsor/co-sponsor team, will
implement a comprehensive training plan focused on improving critical thinking, experimental and analytical
skills, presentation and public speaking skills, and aid in creating a network of colleagues and collaborators.
项目概要/摘要
内源性离子通道活动示踪剂监测缺血性发作期间 Kv2 通道的参与情况
神经元电信号由许多离子通道亚型的联合作用控制。
不同组的离子通道总和创造了神经元电兴奋性的显着多样性。
由于技术限制,剖析离子通道亚型在复杂的过程中的个体作用
我们对生理或病理生理事件的了解仍然有限。
单个内源离子通道亚型的电动力学如何影响全局信号,
尤其是在完整组织或活体动物中,乔恩·萨克博士实验室开发的技术提供了机会。
对整个复杂组织中离子通道亚型的活动进行成像。
Kv2 活性示踪剂 (KAT) 报告内源性神经元钾电压门控离子通道的激活
亚型 2。我们设计了这些 KAT 用于 2 光子成像,并证明 KAT 可以报告
我建议测量大脑切片中内源性神经元 Kv2 离子通道的激活。
模拟病理生理缺血应激下组织切片和活体动物中的离子通道亚型
在大脑中,Kv2 离子通道在大多数(如果不是全部)神经元中高度表达。
被认为对于抑制许多应激(包括缺血性应激)期间的兴奋性毒性信号传导事件至关重要
先前的研究表明,Kv2 离子通道在缺血期间变得非常活跃,抑制攻击。
电兴奋性,并提供神经保护免受兴奋性毒性信号传导的影响。
有证据表明,缺血期间钾通过 Kv2 通道过度流出可引发细胞凋亡
导致神经死亡的级联反应的数量急剧增加。
活跃的 Kv2 通道,但我的博士生从未在复杂组织中实时观察到这一点。
研究 我将探讨模型中 Kv2 离子通道活动的质量激活机制和图像变化
我的研究结果将提高我们对导致神经性中风的分子机制的理解。
中风后细胞死亡,以及 Kv2 通道是否是增加神经元存活的潜在药物靶点
此外,我的研究将是使用荧光探针进行测量的首次尝试。
完整组织中特定离子通道的构象变化并可能改变蛋白质的方式
在整个项目中,申办者/共同申办者团队将在生理背景下研究激活。
实施全面的培训计划,重点提高批判性思维、实验和分析能力
技能、演示和公开演讲技能,以及帮助建立同事和合作者网络。
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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Rebecka Jane Sepela其他文献
Rebecka Jane Sepela的其他文献
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{{ truncateString('Rebecka Jane Sepela', 18)}}的其他基金
Endogenous Ion Channel Activity Tracers to Monitor the Involvement of Kv2 Channels During Ischemic Attack
内源性离子通道活动示踪剂监测缺血性发作期间 Kv2 通道的参与情况
- 批准号:
9925651 - 财政年份:2019
- 资助金额:
$ 3.72万 - 项目类别:
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