Metabolic & Developmental Aspects of Intellectual Disability

这项更新应用代表了一种高度协作的多学科方法，以阐明新生儿缺氧/缺血（H/l）引起的未成熟大脑损伤的分子机制，利用可临床转化的神经保护和神经源性干预。目标是：(1)确定H/l损伤对发育中的大脑的机制；(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)制定临床可行的干预措施，既能单独有效，也能联合有效；(4)确定干预机制和反应的性别差异。基于前一个资助期的进展和新项目研究者产生的结果，研究者假设H/l损伤是由氧化应激、脂质筏-蛋白质相互作用的破坏、急性线粒体损伤后的代谢衰竭和gaba能刺激的衰减等复杂的相互作用引起的。他们还假设，H/l后的最佳神经保护可以通过以下方式实现：避免不必要的高氧，通过给予乙酰左旋肉碱刺激有氧能量代谢，保护脂质层，通过给予萝卜硫素保护基因组抗继发性氧化应激的后处理，以及通过给予雌激素和增强GABA抑制细胞凋亡和刺激神经发生。项目一主要研究代谢衰竭和细胞凋亡的线粒体机制，以及萝卜硫素神经保护的分子基础。项目二主要研究乙酰左旋肉碱对神经元和神经胶质能量代谢、神经递质生物合成以及神经保护的分子基础的早期和长期改变。研究包括一系列体内成像，31P和1H-MR，以及离体13C-NMR光谱。项目三主要研究神经发生，GABA去极化对神经发生的调控，以及雌二醇如何促进神经发生和神经元存活。项目IV主要研究H/l对脂筏-蛋白相互作用和LI细胞粘附分子功能的影响，LI细胞粘附分子是参与神经突生长、神经元可塑性和信号转导途径的关键蛋白。所有项目将使用由Core B支持的新生大鼠H/l模型，以及使用培养的不同体外发育阶段的皮质或海马神经元的常见O2和葡萄糖剥夺模型。所有的项目也被氧化应激、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、保护信号转导或促进神经发生来优化神经系统结果的共同主题联系在一起。

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.