Role of 20-HETE in Pediatric Traumatic Brain Injury
20-HETE 在小儿创伤性脑损伤中的作用
基本信息
- 批准号:9233784
- 负责人:
- 金额:$ 35.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-03-01 至 2021-02-28
- 项目状态:已结题
- 来源:
- 关键词:Adenosine Diphosphate RiboseAdultAdverse effectsAdverse eventAlkane 1-monooxygenaseAnimal ModelAnti-Inflammatory AgentsAnti-inflammatoryArachidonic AcidsAreaAttentionAttenuatedBrainBrain hemorrhageCASP8 geneCaspaseCell DeathCellsCerebral IschemiaChildChildhoodCraniocerebral TraumaCytochrome P450Cytochrome aCytochromesDataDevelopmentDoseEnzymesEventFamilyFemaleGoalsHeart ArrestHippocampus (Brain)HourHydroxyeicosatetraenoic AcidsInfantInflammationInflammatoryInjuryInvestigationIschemic StrokeLeadLearningLesionLifeLipopolysaccharidesLymphocyteMembrane LipidsMicrogliaMixed Function OxygenasesModelingMorphologyN-Methyl-D-Aspartate ReceptorsNADPH OxidaseNa(+)-K(+)-Exchanging ATPaseNeurodegenerative DisordersNeurologicNeuronal InjuryNeuronsNeutrophil InfiltrationNuclearNucleic AcidsOutcomeOxidative StressPathway interactionsPediatric Brain InjuryPharmaceutical PreparationsPhosphorylationPhosphotransferasesPolymersProcessProtein IsoformsProteinsPublic HealthRIPK1 geneRIPK3 geneRattusRecoveryResearchRoleSensorimotor functionsSex CharacteristicsSignal TransductionSocial BehaviorSocial FunctioningStressStrokeSupportive careTestingThalamic structureTherapeuticToddlerTranslationsTraumatic Brain InjuryUnited StatesWorkapoptosis inducing factorbaseclinically relevantcognitive functioncontrolled cortical impactcytokinedisabilityexcitotoxicityimprovedimproved outcomeinhibitor/antagonistinnovationinsightmalememberneonatal hypoxic-ischemic brain injuryneuroinflammationneuron lossneuroprotectionnoveloutcome forecastpediatric traumatic brain injurypostnatalprogramsprogressive neurodegenerationpublic health relevanceresponsetherapeutic targetyoung adult
项目摘要
DESCRIPTION (provided by applicant): Millions of infants, children and young adults are living with disabilities resulting from traumatic brain injury (TBI) in childhood. Following the intial insult, a cascade of secondary events produces progressive neurodegeneration. The developing brain may be uniquely vulnerable to some of these secondary insults, due to maturational features. In the very young, the injury may interfere with the execution of the developmental program later in life, leading to learning, attention, and social behavior abnormalities. Currently, treatment is limited to supportive care. Here, we will investigate novel emerging pathways involving cell signaling by 20- HETE, a cytochrome P450 metabolite of arachidonic acid. We find that specific cytochrome P450s known to synthesize 20-HETE are expressed in neurons and microglia and that 20-HETE can induce phosphorylation of NMDA receptors and Na,K-ATPase. Based on our previous work showing that a 20-HETE inhibitor is neuroprotective in models of neonatal hypoxia-ischemia and adult ischemic and hemorrhagic stroke, we began to study its effect in the controlled cortical impact model in postnatal day 10 rats. Preliminary data show large reductions in lesion volume, improved long-term sensorimotor function, attenuated morphological changes in microglia, and a reduction of pro-inflammatory cytokines. The 20-HETE inhibitor also attenuated the response to lipopolysaccharide in microglia cultures. The goal of this project is to investigate the role of 20-HETE in males and females in a model of pediatric TBI. In Aim 1, we will determine the optimal duration of 20-HETE inhibitor administration and the maximum delay that provides efficacy so as to inform when 20-HETE signaling is exerting adverse effects after TBI. In Aim 2, we will determine the effects of 20-HETE inhibition after TBI on NADPH oxidase and the consequent downstream effects on key caspase-dependent and independent cell death pathways. In Aim 3, we will determine the effects of 20-HETE inhibition after TBI on microglia morphology and the cytokine profile. By targeting both cell death and inflammatory pathways with a single drug in the very immature brain, this work has great potential for improving outcome from TBI in infants and toddlers who often have the poorest prognosis in pediatric TBI. Moreover, emerging evidence with cerebral ischemia indicates sex differences in cell death mechanisms and inflammation in both immature and mature brain, yet sex differences have been understudied in pediatric TBI models. Thus, the proposed work also is innovative in that it will begin to reveal whether sex differences in response to neuroprotective therapies are operative after TBI in the immature brain. Finally, elucidation of new pathways of 20-HETE in neurons and microglia could have an important bearing beyond TBI for other neurodegenerative disorders involving excitotoxicity and neuroinflammation and, hence, may stimulate new areas of investigation.
描述(由申请人提供):数以百万计的婴儿、儿童和年轻人因童年时期的创伤性脑损伤(TBI)而患有残疾,在最初的损伤之后,一系列继发事件会导致进行性神经变性。由于年龄的成熟特征,他们很容易受到一些继发性伤害,这种伤害可能会干扰以后生活中的发育程序的执行,导致学习、注意力和社交行为异常。在这里,我们将研究涉及 20-HETE(花生四烯酸的细胞色素 P450 代谢物)的细胞信号传导的新途径。我们发现已知合成 20-HETE 的特定细胞色素 P450 在神经元和小胶质细胞中表达。 20-HETE 可以诱导 NMDA 受体和 Na,K-ATP 酶的磷酸化,基于我们之前的研究表明 20-HETE 抑制剂具有神经保护作用。在新生儿缺氧缺血和成人缺血性和出血性中风模型中,我们开始在出生后第 10 天的大鼠的受控皮质冲击模型中研究其效果,初步数据显示病变体积大幅缩小,长期感觉运动功能得到改善,形态变化减弱。小胶质细胞中促炎细胞因子的减少也减弱了小胶质细胞中脂多糖的反应。该项目的目标是在儿科 TBI 模型中研究 20-HETE 在男性和女性中的作用。在目标 1 中,我们将确定 20-HETE 抑制剂给药的最佳持续时间和提供疗效的最大延迟时间。以便了解 TBI 后 20-HETE 信号传导何时产生不利影响 在目标 2 中,我们将确定 TBI 后 20-HETE 抑制对 NADPH 氧化酶的影响以及随之而来的下游影响。在目标 3 中,我们将通过使用单一药物同时靶向细胞死亡和炎症途径,确定 TBI 后 20-HETE 抑制对小胶质细胞形态和细胞因子谱的影响。未成熟的大脑,这项工作对于改善婴儿和幼儿的 TBI 结局具有巨大的潜力,因为婴儿和幼儿的 TBI 预后往往最差。此外,脑缺血的新证据表明,两者的细胞死亡机制和炎症存在性别差异。未成熟和成熟的大脑,但在儿科 TBI 模型中尚未充分研究性别差异。因此,这项工作也具有创新性,因为它将开始揭示 TBI 后对神经保护治疗的反应是否存在性别差异。阐明 20-HETE 在神经元和小胶质细胞中的新通路可能对 TBI 之外的涉及兴奋性毒性和神经炎症的其他神经退行性疾病产生重要影响,因此可能会刺激新的研究领域。
项目成果
期刊论文数量(0)
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COURTNEY L ROBERTSON其他文献
COURTNEY L ROBERTSON的其他文献
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{{ truncateString('COURTNEY L ROBERTSON', 18)}}的其他基金
40th National Neurotrauma Society (NNS) Annual Symposium 2023 - Celebrating the Landmarks of Neurotrauma
2023 年第 40 届国家神经创伤协会 (NNS) 年度研讨会 - 庆祝神经创伤的里程碑
- 批准号:
10753817 - 财政年份:2023
- 资助金额:
$ 35.44万 - 项目类别:
Role of 20-HETE in Pediatric Traumatic Brain Injury
20-HETE 在小儿创伤性脑损伤中的作用
- 批准号:
9883849 - 财政年份:2016
- 资助金额:
$ 35.44万 - 项目类别:
Mitochondrial Dysfunction in Pediatric Head Injury
小儿头部损伤中的线粒体功能障碍
- 批准号:
6666677 - 财政年份:2002
- 资助金额:
$ 35.44万 - 项目类别:
Mitochondrial Dysfunction in Pediatric Head Injury
小儿头部损伤中的线粒体功能障碍
- 批准号:
6927046 - 财政年份:2002
- 资助金额:
$ 35.44万 - 项目类别:
Mitochondrial Dysfunction in Pediatric Head Injury
小儿头部损伤中的线粒体功能障碍
- 批准号:
6544206 - 财政年份:2002
- 资助金额:
$ 35.44万 - 项目类别:
Mitochondrial Dysfunction in Pediatric Head Injury
小儿头部损伤中的线粒体功能障碍
- 批准号:
6800065 - 财政年份:2002
- 资助金额:
$ 35.44万 - 项目类别:
Mitochondrial Dysfunction in Pediatric Head Injury
小儿头部损伤中的线粒体功能障碍
- 批准号:
7122130 - 财政年份:2002
- 资助金额:
$ 35.44万 - 项目类别:
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