Role of Microglial Calcium Waves in Ischemic Stroke
小胶质细胞钙波在缺血性中风中的作用
基本信息
- 批准号:10303222
- 负责人:
- 金额:$ 28.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAcuteAddressAffectAmericanAnimalsApoptosisBehavioralBrainCalciumCalcium ChannelCalcium OscillationsCalcium SignalingCause of DeathCell DeathCell SurvivalCell physiologyCellsCerebral IschemiaDevelopmentDiffuseDiseaseFemaleFunctional disorderGeneticHistologicHypoxiaImageImmuneImmune systemImmunoassayInfarctionInflammationInflammatoryInflammatory ResponseInjuryIschemic StrokeLeadMeasuresMediatingMicrogliaMiddle Cerebral Artery OcclusionMolecularMusNecrosisNeurologicNeuronal InjuryNeuronsPathologyPathway interactionsPatternPeriodicalsPharmacologyPhasePilot ProjectsProcessPublic HealthRecurrenceReporterRoleSecondary toSpreading Cortical DepressionStrokeSystemTechniquesTestingTherapeutic InterventionTissuesTransgenic MiceTraumatic Brain InjuryUnited States National Institutes of HealthWorkacute strokebasebehavioral outcomebrain cellbrain parenchymaburden of illnesscalcium indicatorclinical translationcohortcomorbiditycytokinedisabilitygenetic approachimprovedimproved outcomein vivoinhibitor/antagonistinnovationinterestischemic injurymalemouse modelneuroinflammationneuronal survivalnovelnovel therapeutic interventionpost strokepreventprotective effectresponsesingle cell sequencingstroke interventionstroke outcomestroke patienttooltwo photon microscopytwo-photon
项目摘要
Abstract
Ischemic stroke is a leading cause of death and severe disability in US and worldwide. Stroke-induced hypoxia
promotes a cascade of pathophysiological responses that lead to necrosis in the ischemic core, and apoptosis
in the hypo-perfused tissue known as penumbra. Cell death triggers an inflammatory response that contributes
to secondary injury and potentially harms the neurons surviving the initial insult. Microglia are the principal
immune cells in the brain parenchyma but their specific roles in secondary injury and the underlying mechanisms
of induction remain unclear. We hypothesize that increased calcium signaling is a key mechanism in the acute
stroke-induced microglial activation, possibly leading to increased release of proinflammatory cytokines. We
have developed a mouse reporter that indicates intracellular calcium in microglial cells. In this system, we use
2- photon imaging and middle cerebral artery occlusion (MCAo) to study microglial responses to ischemic injury
in vivo. We have demonstrated periodical waves of calcium activity in cortical microglia following intraarterial
occlusion, consistent with patterns of cortical spreading depolarizations (CSD). We propose to test the role of
these calcium transients by pharmacological inhibition of calcium influx, mediated by the calcium release-
activated calcium (CRAC) channels, and by genetic ablation of CRAC channel subunits. In Aim 1, we will directly
test whether the novel CRAC channel inhibitors developed by CalciMedica can reduce microglial activation,
neuro-inflammation and ultimately infarct size in the mouse model of MCAo. Pharmacological effects of these
blockers will be characterized with 2-photon imaging and their immune-protective effects in vivo will be evaluated
by cytokine profiling. In Aim2, the CRAC channel subunits Stim1 and Stim2 will be genetically ablated in brain
microglia and behavioral outcomes and infarct size after MCAo stroke will be evaluated. Stroke kills almost
130,000 Americans each year. If successful, clinical translation of this approach could help to reduce the burden
of this disease. Our overreaching objective is to apply the tools and techniques assembled under this pilot study
to a broader R01 project investigating CRAC-mediated calcium overload in all other brain cells during ischemic
injury.
摘要
在美国和世界范围内,缺血性中风是导致死亡和严重残疾的主要原因。卒中致低氧
促进一连串的病理生理反应,导致缺血核心的坏死和细胞凋亡
在被称为半影区的低血流组织中。细胞死亡触发炎症反应
导致继发性损伤,并可能损害在最初的伤害中幸存下来的神经元。小胶质细胞是主要的
脑实质中的免疫细胞及其在继发性损伤中的特殊作用及其机制
目前尚不清楚诱导作用的大小。我们假设钙信号的增加是急性心肌梗死的关键机制。
中风诱导的小胶质细胞激活,可能导致促炎细胞因子的释放增加。我们
已经开发出一种小鼠报告,可以显示小胶质细胞中的细胞内钙。在这个系统中,我们使用
双光子成像和大脑中动脉阻塞(MCAO)研究小胶质细胞对缺血损伤的反应
在活体内。我们已经证实了动脉插管后皮质小胶质细胞中钙活动的周期性波动。
闭塞,与皮质扩散性去极化(CSD)模式一致。我们建议测试一下
这些钙瞬变是通过药物抑制钙内流,通过钙释放-
激活的钙通道(CRAC),并通过基因消融CRAC通道亚基。在目标1中,我们将直接
测试由CalciMedica开发的新型CRAC通道抑制剂是否可以减少小胶质细胞的激活,
MCAO小鼠模型中的神经炎症和最终的脑梗塞面积。这些化合物的药理作用
阻滞剂将通过双光子成像进行表征,并将在体内评估其免疫保护效果
通过细胞因子图谱。在AIM2中,CRAC通道亚基STIM1和Stim2将在大脑中被基因消融
将评估MCAO卒中后的小胶质细胞和行为结果以及梗塞范围。中风几乎致人死亡
每年有13万美国人。如果成功,这种方法的临床翻译可能有助于减轻负担
这种疾病。我们超乎寻常的目标是应用在这项初步研究下组装的工具和技术
到一个更广泛的R01项目,调查缺血期间CRAC介导的所有其他脑细胞的钙超载
受伤。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Petr Tvrdik其他文献
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{{ truncateString('Petr Tvrdik', 18)}}的其他基金
Role of Microglial Calcium Waves in Ischemic Stroke
小胶质细胞钙波在缺血性中风中的作用
- 批准号:
10418797 - 财政年份:2021
- 资助金额:
$ 28.26万 - 项目类别:
Cre, Dre Dual Lineage Model for Calcium Imaging and Optogenetic Manipulations
用于钙成像和光遗传学操作的 Cre、Dre 双谱系模型
- 批准号:
8493621 - 财政年份:2013
- 资助金额:
$ 28.26万 - 项目类别:
Cre, Dre Dual Lineage Model for Calcium Imaging and Optogenetic Manipulations
用于钙成像和光遗传学操作的 Cre、Dre 双谱系模型
- 批准号:
8657497 - 财政年份:2013
- 资助金额:
$ 28.26万 - 项目类别:
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