Synaptic Circuitry in Stroke
中风中的突触回路
基本信息
- 批准号:10170436
- 负责人:
- 金额:$ 33.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-08-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Brain InjuriesAddressAffectAlgorithmic AnalysisAnionsApoptosisAsphyxiaAstrocytesBrainBrain EdemaBrain InjuriesBrain hemorrhageCarrier ProteinsCell Membrane PermeabilityCell membraneCessation of lifeChloridesClinicalClinical DataComputersCoupledCraniocerebral TraumaDataDendritesDevelopmentEdemaElectron MicroscopyElectrophysiology (science)EventExtracellular SpaceGeneticGrantHeart ArrestHypoxiaImageInjuryIonsIschemiaIschemic StrokeLaser Scanning MicroscopyLaser Speckle ImagingLeadLearningLinkMediatingMetabolicMicroinjectionsMitochondriaModelingMolecularMonitorMorphologyMotionMovementMusNeurogliaNeurologicNeurological emergenciesNeuronsOrganellesPathogenicityPathologicPathway interactionsPatientsPermeabilityPharmaceutical PreparationsPharmacologyPlayPre-Clinical ModelProtonsPumpRecoveryRoleSliceSpecificityStressStrokeStructureSupervisionSwellingTechnologyTestingTherapeutic InterventionThinnessTimeTissuesTransmission Electron MicroscopyTraumaTraumatic Brain InjuryTraumatic injuryTubular formationUncertaintyViralWaterbasebrain cellchloride-cotransporter potassiumconditional knockoutcytokinecytotoxicexperimental studyhemodynamicshippocampal pyramidal neuronimaging studyin vivoinsightischemic injurymortalitymouse geneticsnervous system disorderneural circuitneuronal cell bodyneuronal survivalneuroprotectionnovelreal-time imagestargeted treatmenttherapy designtooltreatment strategytwo photon microscopytwo-photonwater channel
项目摘要
Spreading depolarizations (SDs) that occur in stroke and traumatic brain injury patients exacerbate the neuronal
damage in metabolically compromised tissue. SDs are waves of sustained neuronal and glial depolarization that
actively propagate a breakdown of ion gradients through the injured brain. The ion fluxes during SD are followed
by a rapid accumulation of water inside neurons and astrocytes causing cytotoxic edema. Pyramidal neurons
lack functional aquaporins. This implies that passive osmotically obligated water entry after the ionic movements
during SD is unlikely. Using pharmacological inhibition, we have identified several chloride-coupled
cotransporters that mediate ion and water fluxes and can participate in neuronal swelling. Recently mice with
conditional deletion of these transporter proteins were generated offering unique opportunity to identify the exact
molecular conduits of water influx into neurons during SD, and this will be studied in Aim 1. Cytotoxic edema
distorts intracellular organelles. Mitochondria play a variety of functional roles in neurons, from metabolic support
and neuroprotection to the release of cytokines that trigger apoptosis. In dendrites, the mitochondrial structure
is closely linked to their function, and fragmentation of the normally elongated mitochondria indicates loss of their
function under pathological conditions. To date, fragmentation of mitochondria was studied either in dissociated
cultured neurons or brain slices, but not in the intact living brain. Using real-time in vivo 2-photon microscopy,
we quantified mitochondrial fragmentation during brain injury. We demonstrated that alterations in neuronal
mitochondria morphology occurs within minutes of injury onset and can be reversible in traumatic and ischemic
injuries. Impact of SD on mitochondrial structure could be one of the major factors affecting mitochondrial
fragmentation and neuronal survival during noxious conditions, and it will be examined in aims 2 and 3. The
specific aims are: 1) To identify neuronal chloride cotransporters that are involved in the onset of SD-induced
neuronal swelling. 2) To test the hypothesis that SD is the triggering mechanism of rapid neuronal mitochondrial
fragmentation. 3) To test possible mechanistic links between SD and mitochondrial fragmentation. The proposal
integrates a variety of classic and state of the art technologies; viral expression, mouse genetics, in vivo 2-photon
microscopy coupled with electrophysiology and laser speckle imaging, as well as ultrastructural analyses with
serial section transmission electron microscopy. A novel automatic analysis algorithm, based on supervised
statistical computer learning will be used to quantify the degree of dendritic mitochondrial fragmentation. Model
of transient global ischemia (BCCAO) will be used to evoke SD. In a model of focal stroke (photothrombotic
occlusion) and the healthy cortex, SD will be evoked by KCl microinjection. The results will bring new insight into
the development of cytotoxic edema during the stroke injury. The experiments will also address how and under
what conditions the mitochondrial organelles are affected by SD and reveal mechanistic links between SD and
mitochondrial fragmentation.
中风和创伤性脑损伤患者中发生的扩散去极化(SD)会加剧神经元
代谢受损的组织受到损害。 SD 是持续的神经元和神经胶质去极化波,
通过受伤的大脑积极传播离子梯度的破坏。 SD 期间的离子通量如下
神经元和星形胶质细胞内水分快速积聚,导致细胞毒性水肿。锥体神经元
缺乏功能性水通道蛋白。这意味着离子运动后被动渗透迫使水进入
在SD期间不太可能。通过药理学抑制,我们已经鉴定了几种氯偶联
介导离子和水通量并参与神经元肿胀的协同转运蛋白。最近老鼠与
这些转运蛋白的条件删除为识别确切的转运蛋白提供了独特的机会
SD 期间水流入神经元的分子管道,这将在目标 1 中进行研究。细胞毒性水肿
扭曲细胞内细胞器。线粒体在神经元中发挥多种功能作用,包括代谢支持
以及触发细胞凋亡的细胞因子释放的神经保护作用。在树突中,线粒体结构
与其功能密切相关,正常伸长的线粒体的断裂表明其功能丧失
在病理条件下发挥作用。迄今为止,线粒体碎片的研究要么是在解离的
培养的神经元或脑切片,但不是完整的活体大脑。使用实时体内 2 光子显微镜,
我们量化了脑损伤期间的线粒体碎片。我们证明了神经元的改变
线粒体形态在损伤发生后几分钟内发生,并且在创伤和缺血性损伤中是可逆的
受伤。 SD对线粒体结构的影响可能是影响线粒体的主要因素之一
有害条件下的碎片化和神经元存活,并将在目标 2 和 3 中进行检查。
具体目标是: 1) 鉴定参与 SD 诱导的神经元氯协同转运蛋白
神经元肿胀。 2)检验SD是快速神经元线粒体触发机制的假设
碎片化。 3) 测试SD和线粒体碎片之间可能的机制联系。提案
融合了多种经典和最先进的技术;病毒表达、小鼠遗传学、体内 2 光子
显微镜结合电生理学和激光散斑成像,以及超微结构分析
连续切片透射电子显微镜。一种基于监督的自动分析算法
统计计算机学习将用于量化树突状线粒体碎片的程度。模型
短暂性全身缺血 (BCCAO) 的值将用于诱发 SD。在局灶性中风模型中(光血栓形成
闭塞)和健康皮层,SD 将通过 KCl 显微注射引起。结果将带来新的见解
中风损伤期间细胞毒性水肿的发展。实验还将解决如何以及在什么情况下
线粒体细胞器在什么条件下受到 SD 的影响,并揭示了 SD 和 SD 之间的机制联系
线粒体碎裂。
项目成果
期刊论文数量(0)
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SERGEI A KIROV其他文献
SERGEI A KIROV的其他文献
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{{ truncateString('SERGEI A KIROV', 18)}}的其他基金
Neuroprotection in the Human Brain Tissue Model of Stroke
中风人脑组织模型中的神经保护
- 批准号:
7587139 - 财政年份:2008
- 资助金额:
$ 33.69万 - 项目类别:
Activity and dendritic structural rearrangements in the mature brain
成熟大脑的活动和树突结构重排
- 批准号:
7584090 - 财政年份:2007
- 资助金额:
$ 33.69万 - 项目类别:
Activity and dendritic structural rearrangements in the mature brain
成熟大脑的活动和树突结构重排
- 批准号:
7383760 - 财政年份:2007
- 资助金额:
$ 33.69万 - 项目类别:
Activity and dendritic structural rearrangements in the mature brain
成熟大脑的活动和树突结构重排
- 批准号:
7261793 - 财政年份:2007
- 资助金额:
$ 33.69万 - 项目类别:
Activity and dendritic structural rearrangements in the mature brain
成熟大脑的活动和树突结构重排
- 批准号:
8032549 - 财政年份:2007
- 资助金额:
$ 33.69万 - 项目类别:
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