STIM1-dependent calcium signaling in neuronal responses to hypoxia and ischemia
STIM1 依赖性钙信号传导在神经元对缺氧和缺血反应中的作用
基本信息
- 批准号:9036161
- 负责人:
- 金额:$ 23.85万
- 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:2015-09-15 至 2017-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAtaxiaBiochemicalBrainBrain Hypoxia-IschemiaBrain regionCalciumCalcium SignalingCardiopulmonary ResuscitationCause of DeathCell DeathCell physiologyCellsCerebellar DiseasesCerebellumCessation of lifeDependenceEventFoundationsFunctional disorderGoalsHeart ArrestHippocampus (Brain)HomeostasisHypoxiaImageImpaired cognitionImpairmentIn VitroInjuryIschemiaKnock-outLightMediatingMediator of activation proteinModelingMotorMusMutant Strains MiceNeurologicNeurologic DysfunctionsNeuronal InjuryNeuronsOxygenPhysiologicalPropertyPurkinje CellsRoleSignal PathwaySignal TransductionSliceStrokeSynapsesTemperatureTestingTherapeutic InterventionWorkbasebehavioral studycell injurydeprivationdisabilityhuman STIM1 proteinin vivoinhibitor/antagonistmotor disordermotor impairmentmutantnatural hypothermianeuroprotectionnovelpublic health relevancerelating to nervous systemresponse
项目摘要
DESCRIPTION (provided by applicant): Cardiac arrest and stroke are major causes of death and disability and often result in neurological impairment. Neural damage is often heterogeneous as some regions of the brain are more vulnerable to the hypoxia and ischemia (H-I) caused by these insults. The cerebellum is such a region and hypoxic and ischemic events in the cerebellum often result in ataxia and other problems with motor coordination. Neuronal calcium (Ca2+) dysregulation and Ca2+ overload are recognized as causes of cell death following brain H-I. Recently we identified stromal interaction molecules (STIM) as key components of Ca2+ signaling in excitable cells where they activate refilling of Ca2+ stores during repetitive electrical activity. Given an exceptionally high level of STIM1 expression in cerebellar Purkinje neurons and the selective vulnerability of these neurons to damage by H-I, we hypothesize that STIM1 is essential to refill Ca2+ stores and sustain Ca2+ signaling in Purkinje neurons during periods of intense synaptic activity, as occurs with H-I injury; thus, STIM1-SOCE is a critical mediator of the excitotoxic Ca2+ dysregulation and overload that causes Purkinje neuron injury and death. Our goal is to test this hypothesis by determining the fundamental properties and functions of STIM1-SOCE in Purkinje neurons during physiological and H-I conditions. For this purpose, we will carry out Ca2+ imaging, electrophysiological, morphological, and biochemical studies of cerebellar properties and function, with a focus on Purkinje neurons, in acute brain slices (Aims 1 and 2) and Purkinje neurons and other vulnerable neurons in vivo (Aim 3) in WT and STIM1 mutant mice to address the following specific aims: 1) Determine the fundamental properties and physiological functions of STIM1-dependent SOCE in cerebellar Purkinje cells, 2) Determine the contribution of STIM1-SOCE to H-I induced injury and death of Purkinje neurons in vitro, and 3) Determine the contribution of STIM1 to the neuronal damage and motor and cognitive dysfunction produced by global ischemia in vivo. These studies will begin to elucidate the role of STIM1-SOCE in Purkinje cell Ca2+ homeostasis and cerebellar function under normal physiological conditions and the contribution of STIM1-SOCE to Ca2+ overload, neuronal death, and neurological dysfunction that is produced by hypoxia and ischemia in the cerebellum and other brain regions.
描述(申请人提供):心脏骤停和中风是导致死亡和残疾的主要原因,通常会导致神经损伤。神经损伤通常是异质性的,因为大脑的某些区域更容易受到这些侮辱引起的缺氧和缺血(H-I)的影响。小脑就是这样一个区域,小脑中的缺氧和缺血事件往往会导致共济失调和其他运动协调问题。神经细胞钙调节失调和钙超载被认为是脑缺血后细胞死亡的原因。最近,我们发现间质相互作用分子(STIM)是可兴奋细胞中钙信号的关键成分,在重复的电活动中,它们激活钙离子储存的再充盈。鉴于STIM1在小脑Purkinje神经元中的异常高表达以及这些神经元对H-I损伤的选择性脆弱性,我们假设STIM1对于浦肯野神经元在突触强烈活动期间重新补充钙储存和维持钙信号是必不可少的,就像H-I损伤所发生的那样;因此,STIM1-SOCE是导致Purkinje神经元损伤和死亡的兴奋性钙毒性失调和过载的关键介质。我们的目标是通过确定在生理和H-I条件下浦肯野神经元中STIM1-SOCE的基本属性和功能来检验这一假说。为此,我们将对小脑的特性和功能进行钙成像、电生理、形态和生化研究,重点是急性脑片(AIMS 1和AIMS 2)中的Purkinje神经元以及WT和STIM1突变小鼠的Purkinje神经元和其他在体易损神经元(Aim 3),以解决以下具体目标:1)确定小脑浦肯野细胞中依赖STIM1的SOCE的基本性质和生理功能;2)确定STIM1-SOCE在体外H-I诱导的Purkinje神经元损伤和死亡中的作用。3)确定STIM1在全脑缺血所致的神经元损伤及运动和认知功能障碍中的作用。这些研究将开始阐明STIM1-SOCE在正常生理条件下对Purkinje细胞钙稳态和小脑功能的作用,以及STIM1-SOCE在小脑和其他脑区缺氧和缺血引起的钙超载、神经元死亡和神经功能障碍中的作用。
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)
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PAUL B ROSENBERG其他文献
PAUL B ROSENBERG的其他文献
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{{ truncateString('PAUL B ROSENBERG', 18)}}的其他基金
STIM1-dependent calcium signaling in neuronal responses to hypoxia and ischemia
STIM1 依赖性钙信号传导在神经元对缺氧和缺血反应中的作用
- 批准号:
9137732 - 财政年份:2015
- 资助金额:
$ 23.85万 - 项目类别:
Actigraphic assessment of sleep quality in the A4 trial
A4 试验中睡眠质量的活动记录评估
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8871221 - 财政年份:2015
- 资助金额:
$ 23.85万 - 项目类别:
Actigraphic assessment of sleep quality in the A4 trial
A4 试验中睡眠质量的活动记录评估
- 批准号:
9108796 - 财政年份:2015
- 资助金额:
$ 23.85万 - 项目类别:
DIADS-3: An RCT of venlafaxine for depression in AD
DIADS-3:文拉法辛治疗 AD 抑郁症的随机对照试验
- 批准号:
8237716 - 财政年份:2011
- 资助金额:
$ 23.85万 - 项目类别:
DIADS-3: An RCT of venlafaxine for depression in AD
DIADS-3:文拉法辛治疗 AD 抑郁症的随机对照试验
- 批准号:
8337846 - 财政年份:2011
- 资助金额:
$ 23.85万 - 项目类别:
DIADS-3: An RCT of venlafaxine for depression in AD
DIADS-3:文拉法辛治疗 AD 抑郁症的随机对照试验
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8530135 - 财政年份:2011
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A Theoretically Based Memory Training Intervention in Mild Cognitive Impairment
基于理论的记忆训练干预轻度认知障碍
- 批准号:
8292063 - 财政年份:2010
- 资助金额:
$ 23.85万 - 项目类别:
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- 批准号:
8496095 - 财政年份:2009
- 资助金额:
$ 23.85万 - 项目类别:
The role of STIM1 in cardiac and skeletal muscle function
STIM1 在心脏和骨骼肌功能中的作用
- 批准号:
8733230 - 财政年份:2009
- 资助金额:
$ 23.85万 - 项目类别:
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