Metabolic & Developmental Aspects of Mental Retardation

描述(申请人提供)：这项续展申请代表了一种多学科的方法，以确定调节运输、新陈代谢区隔、能量产生、神经递质和神经递质受体的内源性效应器的合成以及细胞死亡的因素。项目I的研究将集中在大脑间隙中谷氨酰胺形成的谷氨酸的机制和作用。数据表明，在正常的非应激脑和创伤脑中，导致脑细胞外间隙谷氨酸形成的机制是不同的，例如在缺氧/缺血发作后发生的机制。推测可能与依赖磷酸的谷氨酰胺酶和γ-谷氨酰转肽酶有关。这项研究将使用缺氧/缺血大鼠模型和基因敲除小鼠模型。项目二将探讨发育过程中能量代谢、犬尿酸合成和谷氨酸能机制之间的相互关系。犬尿酸是电离子兴奋性氨基酸受体的广谱拮抗剂，在低浓度时优先阻断NMDA受体的甘氨酸共激动剂部位。因此，犬尿酸可能通过调节谷氨酸能神经传递而影响神经元对兴奋性损伤的易感性。缺乏犬尿氨酸生物合成酶的基因敲除小鼠模型增强了对兴奋性毒性的敏感性。项目III中的研究提出了一种假设，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障碍可能会对发育中的大脑造成长期损害，即使在最初的伤害停止后，这种损害也会导致持续的细胞损害。它还将评估这样一种假设，即对大脑来说，维持乳酸的生产和利用的适当平衡是至关重要的，因为这种单羧酸是发育大脑的底物，可能也是成年大脑神经元的底物。生化和核磁共振研究将在缺氧/缺血和低血糖的动物模型中进行。项目IV中的研究将跟进这一重要发现，即未成熟大鼠的脑线粒体在缺氧/缺血模型中对暴露于高水平钙离子引起的生物能衰竭具有抵抗力。这些研究可能导致在新生儿和儿童中开发有针对性的神经保护干预措施。

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.