Astroglial mechanisms in sleep homeostasis
星形胶质细胞睡眠稳态机制
基本信息
- 批准号:10283928
- 负责人:
- 金额:$ 38.25万
- 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:2021-04-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:Alzheimer&aposs DiseaseAlzheimer&aposs disease modelAstrocytesBrainBrain DiseasesCalciumCellsDataDementiaDiseaseElectroencephalographyErythrocytesEtiologyExcisionHomeostasisImageImmune responseImpaired cognitionLaboratoriesLeadLeftMeasurementMeasuresMediatingMicroscopyMolecularMorphologyNerve DegenerationNeurodegenerative DisordersNeurogliaNeurologic ProcessNeuronsPlayPolysomnographyProcessProteinsPublicationsRegulationRoleSignal PathwaySleepSleep DeprivationSynapsesSynaptic plasticityTestingWakefulnessbrain cellbrain metabolismcommon symptomfallsin vivoinsightminiaturizemouse modelneuroinflammationneuron lossneuronal metabolismnovel therapeutic interventionparent grantsleep abnormalitiessleep regulationsynaptic pruningtwo photon microscopy
项目摘要
Summary
Our parent grant NS114780 will determine cellular and molecular signaling pathways in astrocytes important in
mammalian sleep regulation. We now extend our approach to neurodegenerative diseases, with a focus on
mouse models of Alzheimer’s.
Sleep may play an important role in the etiology and progression of neurodegenerative disease. Abnormal
sleep is a common symptom of many neurodegenerative diseases including Alzheimer’s. Sleep also influences
several neurological processes that if perturbed may contribute to cognitive decline and dementia. Among
these are synaptic morphology/plasticity, immune response/neuroinflammation, brain metabolism and protein
clearance. Therefore, understanding how sleep and sleep loss impact the diseased brain may provide new
insights into Alzheimer’s and related diseases. This requires an understanding of how different classes of brain
cells operate during sleep.
The glial cells known as astrocytes are particularly important to examine in this context. Astrocytes mediate
several processes dysregulated in Alzheimer’s (e.g. synaptic pruning, neuronal metabolism and removal of
plaque proteins and are abnormally hyper-reactive in neurodegenerative disease (as measured by increased
intracellular Ca2+. Astrocyte hyper-reactivity may in turn disrupt these normal processes vital to brain function.
We have shown that astrocytes play central roles in mammalian sleep regulation. We have also recently
demonstrated that sleep normally reduces (clears) astrocyte intracellular Ca2+ concentrations that accumulate
during wakefulness [18]. We hypothesize that in Alzheimer’s the regulation of intracellular Ca2+ in astrocytes
during sleep is abnormal leading to astrocytic hyper-reactivity. We will test this hypothesis by
Impact: Sleep and astrocytes are implicated in neurodegenerative diseases like Alzheimer’s. Recent findings
from our laboratory indicate that astrocytes influence sleep. This indicates that astrocytes may mediate
important sleep functions that are relevant to neurodegenerative diseases. The requisite step to exploring this
possibility is to examine the activity of these glial cells during sleep in mouse models of neurodegenerative
disease. Our hypothesis is that sleep loss results in a persistent activation of astrocytes in neurodegenerative
disease, which in turn could lead to neuronal cell death. If true, our findings will be impactful because they will
identify a heretofore poorly understood interaction between sleep and glia that can be leveraged for new
therapeutic approaches to Alzheimer’s.
总结
我们的母基金NS 114780将确定星形胶质细胞中重要的细胞和分子信号通路,
哺乳动物的睡眠调节我们现在将我们的方法扩展到神经退行性疾病,重点是
老年痴呆症的小鼠模型。
睡眠可能在神经退行性疾病的病因和进展中起重要作用。异常
睡眠是包括阿尔茨海默氏症在内许多神经退行性疾病的常见症状。睡眠也会影响
如果受到干扰,可能导致认知能力下降和痴呆的几种神经过程。之间
这些是突触形态/可塑性、免疫反应/神经炎症、脑代谢和蛋白质
间隙因此,了解睡眠和睡眠不足如何影响患病的大脑可能会提供新的
对老年痴呆症及相关疾病的深入了解。这需要了解不同类别的大脑
细胞在睡眠中工作。
在这种情况下,被称为星形胶质细胞的神经胶质细胞尤其重要。星形胶质细胞介导
阿尔茨海默氏症中的几个过程失调(例如突触修剪,神经元代谢和去除神经元)。
斑块蛋白,并且在神经退行性疾病中是异常高反应性的(如通过增加的
胞内Ca 2+。星形胶质细胞的高反应性可能反过来破坏这些对大脑功能至关重要的正常过程。
我们已经表明,星形胶质细胞在哺乳动物的睡眠调节中发挥着重要作用。我们最近还
研究表明,睡眠通常会减少(清除)星形胶质细胞内积累的Ca 2+浓度,
[2018 - 12 - 18]我们推测,在阿尔茨海默氏症中,星形胶质细胞细胞内Ca 2+的调节
在睡眠期间是异常的,导致星形胶质细胞的高反应性。我们将通过以下方式检验这一假设:
影响:睡眠和星形胶质细胞与阿尔茨海默氏症等神经退行性疾病有关。最近的调查结果
表明星形胶质细胞影响睡眠。这表明星形胶质细胞可能介导
重要的睡眠功能与神经退行性疾病有关。探索这一点的必要步骤
一种可能性是在神经退行性疾病的小鼠模型中检查这些神经胶质细胞在睡眠期间的活动。
疾病我们的假设是,睡眠不足导致神经退行性疾病中星形胶质细胞的持续激活。
疾病,这反过来又可能导致神经细胞死亡。如果是真的,我们的发现将产生影响,因为它们将
确定迄今为止对睡眠和神经胶质之间的相互作用知之甚少,
阿尔茨海默氏症的治疗方法
项目成果
期刊论文数量(0)
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会议论文数量(0)
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{{ truncateString('MARCOS G FRANK', 18)}}的其他基金
Exploratory studies of spontaneous cortical activity in visual cortical development
视觉皮层发育中自发皮层活动的探索性研究
- 批准号:
10527992 - 财政年份:2022
- 资助金额:
$ 38.25万 - 项目类别:
Exploratory studies of spontaneous cortical activity in visual cortical development
视觉皮层发育中自发皮层活动的探索性研究
- 批准号:
10684752 - 财政年份:2022
- 资助金额:
$ 38.25万 - 项目类别:
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