Metabolic & Developmental Aspects of Mental Retardation

描述（由申请人提供）：本更新申请代表了一种多学科方法，用于确定调节转运、代谢区室化、能量产生、神经递质合成和神经递质受体内源性效应物以及细胞死亡的因素。 项目I的研究重点是谷氨酰胺在脑间隙形成谷氨酸的机制和作用。 数据表明，导致谷氨酸在脑细胞外空间中形成的机制在正常的无应激脑和创伤脑中是不同的，例如在缺氧/缺血发作后发生。 据推测，磷酸依赖性转氨酶和γ-谷氨酰转肽酶参与。 本研究将使用缺氧/缺血大鼠模型和基因敲除小鼠模型。 项目II将解决在发展过程中的能量代谢，犬尿烯酸合成和代谢能机制之间的相互关系。 犬尿烯酸是离子型兴奋性氨基酸受体的广谱拮抗剂，并且在低浓度下优先阻断NMDA受体的甘氨酸共激动剂位点。 因此，犬尿烯酸可能会影响神经元的脆弱性兴奋性损伤作为一个调制器的兴奋性神经传递。 缺乏犬尿氨酸生物合成酶的基因敲除小鼠模型对兴奋性毒性的敏感性增强。 项目III中的研究提出了这样的假设，即能量代谢、神经元/神经胶质代谢运输和神经递质生物合成的损伤可能导致发育中大脑的长期损伤，即使在初始损伤停止后也会导致持续的细胞损伤。 它还将评估假设，这是至关重要的大脑保持乳酸的生产和利用的适当平衡，因为这种一元羧酸是大脑发育的底物，并可能在成人大脑的神经元。 将在缺氧/缺血和低血糖的动物模型中进行生化和NMR研究。 项目IV的研究将跟进一项重要发现，即未成熟大鼠的脑线粒体对缺氧/缺血模型中暴露于高水平Ca++引起的生物能量衰竭具有抵抗力。 这些研究可能会导致新生儿和儿童有针对性的神经保护干预措施的发展。

DESCRIPTION (provided by applicant): This renewal application represents a multidisciplinary approach to determine factors that regulate transport, metabolic compartmentation, energy production, synthesis of neurotransmitters and endogenous effectors of neurotransmitter receptors, and cell death. The studies in Project I will focus on mechanisms and role of glutamate formed from glutamine in the interstitial space of the brain. Data suggest that the mechanisms leading to the formation of glutamate in the extracellular space of the brain are different in the normal unstressed brain and in the traumatized brain, such as occur following an episode of hypoxia/ischemia. It is hypothesized that phosphate-dependent glutaminase and gamma-glutamyl transpeptidase are involved. A hypoxia/ischemia rat model and a knock-out mouse models will be used in the study. Project II will address the interrelation among energy metabolism, kynurenic acid synthesis, and glutamatergic mechanisms during development. Kynurenic acid is a broad-spectrum antagonist of the ionotropic excitatory amino acid receptors and preferentially blocks the glycine co-agonist site of NMDA receptors at low concentrations. Therefore, kynurenic acid may influence neuronal vulnerability to excitatory insults by functioning as a modulator of glutamatergic neurotransmission. A knock-out mouse model lacking the enzyme for kynurenine biosynthesis has enhanced sensitivity to excitotoxicity. Studies in Project III address the hypothesis that impairment in energy metabolism, neuronal/glial metabolic trafficking, and neurotransmitter biosynthesis may result in long-term damage to developing brain that result in ongoing cellular damage even after the initial insult has ceased. It will also assess the hypothesis that it is crucial for the brain to maintain the proper balance of production and utilization of lactate, since this monocarboxylic acid is a substrate for developing brain, and possibly for neurons in adult brain. Biochemical and NMR studies will be addressed in animal models of hypoxia/ischemia and hypoglycemia. Studies in Project IV will follow up on the important finding that brain mitochondria from immature rats exhibit resistance to bioenergetic failure caused by exposure to high levels of Ca++ in a hypoxia/ischemia model. These studies may lead to the development of targeted neuroprotective interventions in neonates and children.