Metabolic & Developmental Aspects of Mental Retardation

新陈代谢

• 批准号: 6855119
• 负责人: H. Ronald Zielke
• 金额: $ 130.78万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6855119
• 关键词: bioenergetics; brain metabolism; clinical research; glutamates; mental retardation

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.

描述（由申请人提供）：此更新应用代表了一种多学科方法，用于确定调节转运，代谢区室，能量产生，神经递质的合成以及神经递质受体的内源性效应的因素和细胞死亡。 项目研究中的研究将重点介绍由谷氨酰胺在大脑间质空间中形成的谷氨酸的机理和作用。 数据表明，导致大脑细胞外空间中谷氨酸形成的机制在正常的无压力大脑和受创伤的大脑中是不同的，例如在低氧/缺血发作之后发生。 假设涉及磷酸盐依赖性谷氨酰胺酶和γ-谷氨酰基肽酶。 该研究将使用低氧/缺血大鼠模型和敲除小鼠模型。 项目II将在发育过程中解决能量代谢，金尿酸合成和谷氨酸能机制之间的相互关系。 Kynurenic Acid是离子兴奋性氨基酸受体的宽光谱拮抗剂，优先在低浓度下阻止NMDA受体的甘氨酸共振能位点。 因此，雌二酸可能会通过充当谷氨酸能神经传递的调节剂来影响神经元脆弱性对兴奋性侮辱的脆弱性。 缺乏kynurenine生物合成酶的敲除小鼠模型具有对兴奋性毒性的敏感性。 项目III中的研究解决了以下假设：能量代谢，神经/神经胶质代谢运输和神经递质生物合成的损害可能会导致对大脑发育的长期损害，从而导致持续的细胞损害，即使最初的损害已经停止。 它还将评估以下假设：大脑保持乳酸的适当生产和利用的适当平衡至关重要，因为这种单羧酸是发展大脑的底物，并且可能对成人大脑中的神经元而言。 生化和NMR研究将在低氧/缺血和低血糖的动物模型中解决。 项目IV的研究将跟进以下重要发现，即未成熟大鼠的脑线粒体表现出对低氧/缺血模型中高水平Ca ++的抗性生物能衰竭的抗性。 这些研究可能导致在新生儿和儿童中发展有针对性的神经保护干预措施。