Metabolic & Developmental Aspects of Mental Retardation

新陈代谢

• 批准号: 7367929
• 负责人: H. Ronald Zielke
• 金额: $ 132.04万
• 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 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7367929
• 关键词: Metabolic; Developmental; Aspects; 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）：本更新申请代表了一种多学科方法，用于确定调节运输、代谢区室、能量产生、神经递质合成和神经递质受体内源效应器以及细胞死亡的因素。 项目一的研究将集中于谷氨酰胺在大脑间隙中形成谷氨酸的机制和作用。 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未受应激的大脑和受创伤的大脑中是不同的，例如在缺氧/缺血发作后发生的大脑。 据推测，磷酸盐依赖性谷氨酰胺酶和γ-谷氨酰转肽酶参与其中。 该研究将使用缺氧/缺血大鼠模型和基因敲除小鼠模型。 项目 II 将解决开发过程中能量代谢、犬尿酸合成和谷氨酸机制之间的相互关系。 Kynurenic Acid 是离子型兴奋性氨基酸受体的广谱拮抗剂，并在低浓度下优先阻断 NMDA 受体的甘氨酸共激动剂位点。 因此，犬尿酸可能通过充当谷氨酸能神经传递调节剂来影响神经元对兴奋性损伤的脆弱性。 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 的研究提出了这样的假设：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受损可能会对发育中的大脑造成长期损害，从而导致持续的细胞损伤，即使在最初的损伤停止后也是如此。 它还将评估以下假设：维持乳酸产生和利用的适当平衡对于大脑至关重要，因为这种一元羧酸是发育中的大脑的底物，并且可能是成人大脑中神经元的底物。 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 的研究将跟进这一重要发现，即未成熟大鼠的脑线粒体表现出对缺氧/缺血模型中暴露于高水平 Ca++ 引起的生物能衰竭的抵抗力。 这些研究可能会导致针对新生儿和儿童的有针对性的神经保护干预措施的发展。