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: 9233784
• 负责人: COURTNEY L ROBERTSON
• 金额: $ 35.44万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9233784
• 关键词: Adenosine Diphosphate Ribose; Adult; Adverse effects; Adverse event; Alkane 1-monooxygenase; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Area; Attention; Attenuated; Brain; Brain hemorrhage; CASP8 gene; Caspase; Cell Death; Cells; Cerebral Ischemia; Child; Childhood; Craniocerebral Trauma; Cytochrome P450; Cytochrome a; Cytochromes; Data; Development; Dose; Enzymes; Event; Family; Female; Goals; Heart Arrest; Hippocampus (Brain); Hour; Hydroxyeicosatetraenoic Acids; Infant; Inflammation; Inflammatory; Injury; Investigation; Ischemic Stroke; Lead; Learning; Lesion; Life; Lipopolysaccharides; Lymphocyte; Membrane Lipids; Microglia; Mixed Function Oxygenases; Modeling; Morphology; N-Methyl-D-Aspartate Receptors; NADPH Oxidase; Na(+)-K(+)-Exchanging ATPase; Neurodegenerative Disorders; Neurologic; Neuronal Injury; Neurons; Neutrophil Infiltration; Nuclear; Nucleic Acids; Outcome; Oxidative Stress; Pathway interactions; Pediatric Brain Injury; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Polymers; Process; Protein Isoforms; Proteins; Public Health; RIPK1 gene; RIPK3 gene; Rattus; Recovery; Research; Role; Sensorimotor functions; Sex Characteristics; Signal Transduction; Social Behavior; Social Functioning; Stress; Stroke; Supportive care; Testing; Thalamic structure; Therapeutic; Toddler; Translations; Traumatic Brain Injury; United States; Work; apoptosis inducing factor; base; clinically relevant; cognitive function; controlled cortical impact; cytokine; disability; excitotoxicity; improved; improved outcome; inhibitor/antagonist; innovation; insight; male; member; neonatal hypoxic-ischemic brain injury; neuroinflammation; neuron loss; neuroprotection; novel; outcome forecast; pediatric traumatic brain injury; postnatal; programs; progressive neurodegeneration; public health relevance; response; therapeutic target; young adult

 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）：数百万婴儿、儿童和年轻人因童年创伤性脑损伤（TBI）而残疾。在最初的损伤之后，一连串的继发性事件产生进行性神经变性。发育中的大脑可能由于成熟的特征而特别容易受到这些二次伤害。在非常年轻的时候，损伤可能会干扰以后生活中发育计划的执行，导致学习，注意力和社会行为异常。目前，治疗仅限于支持性护理。在这里，我们将研究新的新兴途径，涉及细胞信号的20- HETE，细胞色素P450的代谢物花生四烯酸。我们发现已知合成20-HETE的特异性细胞色素P450在神经元和小胶质细胞中表达，并且20-HETE可以诱导NMDA受体和Na，K-ATP酶的磷酸化。基于我们先前的工作表明20-HETE抑制剂在新生儿缺氧缺血和成人缺血性和出血性中风模型中具有神经保护作用，我们开始研究其在出生后10天大鼠的受控皮质撞击模型中的作用。初步数据显示病变体积大幅减少，长期感觉运动功能改善，小胶质细胞形态学变化减弱，促炎细胞因子减少。20-HETE抑制剂还减弱了小胶质细胞培养物对脂多糖的反应。本项目的目标是研究20-HETE在儿童TBI模型中对男性和女性的作用。在目标1中，我们将确定20-HETE抑制剂施用的最佳持续时间和提供功效的最大延迟，以便告知TBI后20-HETE信号传导何时发挥不良作用。在目标2中，我们将确定TBI后20-HETE抑制对NADPH氧化酶的影响，以及随后对关键的半胱天冬酶依赖性和非依赖性细胞死亡途径的下游影响。在目标3中，我们将确定TBI后20-HETE抑制对小胶质细胞形态和细胞因子谱的影响。通过在非常不成熟的大脑中使用单一药物靶向细胞死亡和炎症途径，这项工作具有改善婴儿和幼儿TBI预后的巨大潜力，这些婴儿和幼儿通常在儿科TBI中预后最差。此外，脑缺血的新证据表明，在未成熟和成熟的大脑中，细胞死亡机制和炎症存在性别差异，但在儿科TBI模型中，性别差异尚未得到充分研究。因此，所提出的工作也是创新的，因为它将开始揭示在未成熟的大脑中TBI后对神经保护治疗的反应的性别差异是否有效。最后，阐明20-HETE在神经元和小胶质细胞的新途径可能有一个重要的轴承超越TBI的其他神经退行性疾病，涉及兴奋性毒性和神经炎症，因此，可能会刺激新的研究领域。