Metabolic & Developmental Aspects of Intellectual Disability

这一更新应用代表了一种高度协作的多学科方法，利用可临床翻译的神经保护和神经源性干预措施，阐明新生儿缺氧/缺血(H/L)导致未成熟脑损伤的分子机制。我们的目标是(1)确定H/L对发育中脑的损伤机制，(2)确定复苏高氧对损伤机制、神经发生和长期结果的影响，(3)开发单独有效和联合有效的临床现实干预措施，(4)表征机制和干预反应的性别差异。基于前一次拨款期间的进展和新项目调查人员产生的结果，研究人员假设H/L损伤是由氧化应激、脂筏-蛋白质相互作用中断、急性线粒体损伤后的代谢衰竭和GABA能刺激减弱之间的复杂相互作用引起的。他们还假设，通过避免不必要的高氧，通过给予乙酰肉碱刺激有氧能量代谢，保护脂筏，通过给予萝卜硫素进行基因组后处理以对抗二次氧化应激，以及通过给予雌二醇和增强GABA来抑制细胞凋亡和刺激神经发生，可以实现对H/L的最佳神经保护。项目I的重点是代谢失败和细胞凋亡的线粒体机制，以及萝卜硫素保护神经的分子基础。项目II侧重于神经元和神经胶质能量代谢、神经递质生物合成的早期和长期变化，以及乙酰肉碱保护神经的分子基础。研究包括体内系列成像、31P和1H-MR以及体外13C-核磁共振波谱。项目III侧重于神经发生，通过去极化GABA对其进行调控，以及雌二醇如何促进神经发生和神经元存活。项目IV重点研究H/L对脂筏-蛋白质相互作用和LI细胞黏附分子功能的影响，LI细胞黏附分子是参与轴突生长、神经元可塑性和信号转导途径的关键蛋白质。所有项目都将使用由Core B支持的新生大鼠H/L模型，以及使用体外培养的不同发育阶段的皮质或海马神经元的常见氧气和葡萄糖剥夺模型。所有项目还通过氧化应激这一共同主题联系在一起，性别对机制和结果的影响，以及通过保护细胞死亡、保护线粒体蛋白质、保护信号转导或促进神经发生来优化神经学结果。

This renewal application represents a highly collaborative, multidisciplinary approach to elucidate molecular mechanisms of injury to the immature brain caused by neonatal hypoxic/ischemia (H/l), utilizing neuroprotective and neurogenic interventions that can be clinically translated. The goals are to (1) identify mechanisms of H/l injury to the developing brain, (2) identify the effects of resuscitative hyperoxia on injury mechanisms, neurogenesis, and long-term outcome, (3) develop clinically-realistic interventions that are effective both alone and in combination, and (4) characterize gender-dependent differences in mechanisms and responses to intervention. Based on progress made during the previous grant period and on results generated by the new project investigators, the investigators hypothesize that H/l injury is caused by complex interactions among oxidative stress, disruption of lipid raft-protein interactions, metabolic failure subsequent to acute mitochondrial injury, and attenuation of GABAergic stimulation. They also hypothesize that optimal neuroprotection following H/l can be achieved by avoiding unnecessary hyperoxia, stimulating aerobic energy metabolism by administration of acetyl-L-carnitine, protecting lipid rafts, genomic post-conditioning against secondary oxidative stress by administration of sulforaphane, and inhibition of apoptosis and stimulation of neurogenesis by administration of estradiol and enhancement of GABA. Project I focuses on mitochondrial mechanisms of metabolic failure and apoptosis, and on the molecular basis for neuroprotection by sulforaphane. Project II focuses on early and long-term alterations in neuronal and glial energy metabolism, neurotransmitter biosynthesis, and the molecular basis for neuroprotection by acetyl-L-carnitine. Studies include serial in vivo imaging, 31P and 1H-MR, and ex vivo 13C-NMR spectroscopy. Project III focuses on neurogenesis, its regulation by depolarizing GABA, and how estradiol can promote neurogenesis and neuronal survival. Project IV focuses on the effects of H/l on lipid raft-protein interactions and function of the LI cell adhesion molecule, a key protein involved in neurite outgrowth, neuronal plasticity, and signal transduction pathways. All projects will use the neonatal rat H/l model, supported by Core B, and a common O2 and glucose deprivation model using cultured cortical or hippocampal neurons at different stages of in vitro development. All projects are also tied together by the common theme of oxidative stress, the effects of gender on mechanisms and outcome, as well as optimization of neurologic outcome by protection against cell death, protecting mitochondrial proteins, preserving signal transduction, or promotion of neurogenesis.