Project I- Impact of Hypoxia-Ischemia and/or Inflammation on Microglia in Cerebellum
项目 I- 缺氧缺血和/或炎症对小脑小胶质细胞的影响
基本信息
- 批准号:9543513
- 负责人:
- 金额:$ 25.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AddressAntibioticsAromataseBehaviorBehavioralBirthBrainBrain Hypoxia-IschemiaBrain regionCeftriaxoneCell CountCellsCellular StressCerebellar NucleiCerebellar vermis structureCerebellumCholineDataDevelopmentDinoprostoneDiseaseDropsEnzymesEstradiolEstrogen ReceptorsFemaleGlutamate TransporterGolgi ApparatusHealthHistologicHumanHypoxiaHypoxic-Ischemic Brain InjuryImmuneImpaired cognitionInfantInflammationInflammatoryInjuryLabelLipidsMembrane LipidsMembrane MicrodomainsMetabolismMicrogliaMinocyclineMorphologyMotorNeuronsPerinatalPerinatal HypoxiaPhagocytesPhagocytosisPhosphatidylserinesPlayProductionProstaglandin ProductionRattusRecoveryRiskRoleSex CharacteristicsSignal TransductionSourceSurveysTetracyclinesTherapeuticTimeTreatment EfficacyTreesbasedietary supplementsexperimental studygranule cellinhibitor/antagonistinsightmalemorphometrynatural hypothermianeonatal hypoxic-ischemic brain injuryneuron developmentneuronal growthnovelpostnatalprotective effectpupreceptor expressionreconstructionsynaptogenesistherapeutic target
项目摘要
PROJECT SUMMARY:
Sensitive periods in neuronal development vary by brain region, sensitivity and vulnerability to disruptive agents. We
have discovered that the second postnatal week in the rat is a sensitive period in cerebellar development to
dysregulation by inflammation. This sensitive period is characterized by increased production of prostaglandins, in
particular PGE2. This sensitive period coincides with a time of increased risk for perinatal H/I (e.g. birth in human
infants). The source of the stunting of the Purkinje neuron dendritic tree following inflammation is unknown. Microglia
are the brains innate immune cells and serve a variety of functions in both health and disease. We have observed tightly
regulated and temporally controlled phagocytic activity of microglia in the developing cerebellum and we hypothesize
this plays an important role in normal cerebellar development. We provide evidence that H/I at PN10 increases still
further the peak in phagocytosis normally seen at PN17. One of the key signals regulating microglia phagocytic activity is
the membrane lipid phosphatidylserine, which is externalized to the outer leaflet and promotes phagocytosis. Hypoxia
has been known to stimulate phagocytosis by stressing cells sufficiently to externalize phosphotidylserine. The role of
metabolism or lipid rafts in the externalization of this lipid has not been considered, nor have either of these variables
been characterized in microglia in a surveying versus activated state.
Hypoxic-Ischemic brain injury often occurs following an inflammatory insult, resulting in further injury than would
otherwise occur. Whether this is true in the developing cerebellum has not been carefully explored nor have sex
differences in hypoxic-ischemic brain or inflammatory injury been considered. We propose three Specific Aims focused
on 1) morphometery of Purkinje neurons, granule cells and the deep cerebellar nuclei following H/I with and without
inflammation, 2) the role of microglia in neuronal damage induced by H/I with and without inflammation and 3) the
impact of tetracycline based antibiotic, Minocycline, as proof of principle and the glutamate transporter modifying
antibiotic Ceftriaxone as a potential therapeutic. We will also explore the dietary supplement, choline and conduct
behavioral and histological analyses to assess injury and recovery. Data generated by these experiments will provide
novel insights into the impact of H/I on the cerebellum and the degree to which it contributes to the impaired cognitive
and motor function seen in infants suffering hypoxic-ischemic encephalopathy.
项目概要:
神经元发育的敏感期因大脑区域、对破坏性物质的敏感性和脆弱性而异。我们
发现大鼠出生后第二周是小脑发育的敏感期,
由炎症引起的失调。这一敏感时期的特征是,
特别是PGE 2。这一敏感期与围产期H/I风险增加的时间相吻合(例如,人类的出生)。
婴儿)。炎症后浦肯野神经元树突树发育迟缓的原因尚不清楚。小胶质
是大脑的先天免疫细胞,在健康和疾病中发挥着各种功能。我们仔细观察了
调节和时间控制的吞噬活动的小胶质细胞在发展中的小脑,我们假设
这在正常小脑发育中起着重要作用。我们提供的证据表明,在PN 10的H/I仍然增加
此外,通常在PN 17看到的吞噬作用的峰值。调节小胶质细胞吞噬活性的关键信号之一是
膜脂质磷脂酰丝氨酸,其外化到外小叶并促进吞噬作用。缺氧
已知通过对细胞施加足够的应力以使磷脂酰丝氨酸外化来刺激吞噬作用。的作用
没有考虑这种脂质外化的代谢或脂筏,也没有考虑这些变量
在小胶质细胞中的特征是处于测量与激活状态。
缺氧缺血性脑损伤通常发生在炎症损伤之后,导致比正常情况下更进一步的损伤。
否则发生。这在发育中的小脑中是否是真的还没有被仔细探索过,也没有性行为。
缺氧缺血性脑损伤或炎性损伤的差异。我们提出了三个具体目标,
(1)H/I后浦肯野神经元、颗粒细胞和小脑深核的形态计量学变化
炎症,2)小胶质细胞在有和没有炎症的H/I诱导的神经元损伤中的作用,以及3)小胶质细胞在炎症中的作用。
四环素类抗生素米诺环素作为原理证明的影响和谷氨酸转运蛋白修饰
抗生素头孢曲松作为一种潜在的治疗。我们还将探讨膳食补充剂,胆碱和行为
行为和组织学分析以评估损伤和恢复。这些实验产生的数据将提供
对H/I对小脑的影响及其对认知功能受损的影响程度的新见解
以及缺氧缺血性脑病患儿的运动功能。
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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MARGARET M. MCCARTHY其他文献
MARGARET M. MCCARTHY的其他文献
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{{ truncateString('MARGARET M. MCCARTHY', 18)}}的其他基金
Project I- Impact of Hypoxia-Ischemia and/or Inflammation on Microglia in Cerebellum
项目 I- 缺氧缺血和/或炎症对小脑小胶质细胞的影响
- 批准号:
9979920 - 财政年份:2016
- 资助金额:
$ 25.65万 - 项目类别:
Endocannabinoids regulate microglia in developing brain
内源性大麻素调节大脑发育中的小胶质细胞
- 批准号:
9028927 - 财政年份:2016
- 资助金额:
$ 25.65万 - 项目类别:
Endocannabinoids regulate microglia in developing brain
内源性大麻素调节大脑发育中的小胶质细胞
- 批准号:
10386019 - 财政年份:2016
- 资助金额:
$ 25.65万 - 项目类别:
Endocannabinoids regulate microglia in developing brain
内源性大麻素调节大脑发育中的小胶质细胞
- 批准号:
10627742 - 财政年份:2016
- 资助金额:
$ 25.65万 - 项目类别:
Neurogenesis Following Hypoxic Ischemic Neonatal Brain Injury
新生儿缺氧缺血性脑损伤后的神经发生
- 批准号:
8067623 - 财政年份:2011
- 资助金额:
$ 25.65万 - 项目类别:
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