Interrelationship of Monocarboxylic Acids and Amino Acid in Metabolism traf in Br

项目III中的研究解决了这样的假设，即侮辱扰乱大脑中葡萄糖的供应或代谢将导致能量代谢、神经元/神经胶质代谢运输和神经递质生物合成的急性损害，并可能导致对发育中的大脑的长期损害。神经细胞死亡与缺氧/缺血、低血糖发作和一些先天错误相关，部分原因可能是代谢的长期变化导致持续的细胞损伤，即使在最初的伤害停止后也是如此。近期临床研究 研究人员发现，儿童反复发生的低血糖发作会导致轻度到严重的学习障碍。发育迟缓或过早死亡与先天缺陷有关，这些缺陷损害了葡萄糖的氧化代谢，或阻止了丙酮酸在大脑中的葡萄糖代谢途径中的使用。我们还将讨论这一假设，即大脑保持乳酸的适当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，可能是成人大脑中的神经元的底物。脑乳酸升高是导致智力低下的许多疾病的一个显著特征，并与贫穷有关 神经发育结局高危婴儿。虽然一元羧酸(酮体和乳酸)是发育中的大脑用于能量、神经递质和脂肪生物合成的关键底物，但持续的葡萄糖供应对发育中的大脑至关重要。在大脑能量状态和犬尿酸的合成之间也存在有趣的相互关系，犬尿酸是兴奋性突触的内源性神经调节剂。因此，缺乏犬尿酸的主要生物合成酶Kat II的小鼠，表现出葡萄糖和乳酸代谢受损，并增加了对发育中大脑的兴奋性毒性损伤的敏感性。以下具体目标将检验这些假说，并提供关于发育中脑损伤后脑代谢、线粒体功能和神经元/神经胶质相互作用变化的有价值的新信息。1.确定长期过量产生乳酸对Kat II基因敲除小鼠脑内乳酸处置的影响；2.使用标记底物，通过体外13C-核磁共振波谱测定低血糖、缺氧/缺血和Kat II基因敲除小鼠脑内的代谢、神经元/神经胶质运输和神经递质合成； 测定低血糖或缺氧/缺血后脑线粒体功能代谢的急性变化；4.检测神经保护化合物乙酰肌醇-L-卡尼汀改善缺氧/缺血脑组织代谢改变的能力。从这些研究中获得的信息，以及该计划项目的其他部分，将为未成熟大脑的损伤机制提供新的见解，并将有助于制定神经保护策略。

Studies in Project III address the hypothesis that insults that disrupt the supply or metabolism of glucose in brain will lead to acute impairment in energy metabolism, neuronal/glial metabolic trafficking and neurotransmitter biosynthesis and may also result in long term damage to developing brain. The neural cell death associated with hypoxia/ischemia, hypoglycemic episodes and some inborn errors may be due in part to prolonged alterations in metabolism that result in ongoing cellular damage even after the initial insult has ceased. Recent clinical studies have found that recurrent hypoglycemic episodes in children lead to mild to severe learning impairment. Retardation or early death is associated with inborn errors that impair the oxidative metabolism of glucose or prevent the use of pyruvate from glucose metabolism in anaplerotic pathways in brain. We will also address 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, possibly for neurons in adult brain. Elevated brain lactate is a prominent feature in many disorders that lead to mental retardation, and is associated with poor neurodevelopmental outcome high-risk infants. Although monocarboxylic acids (ketone bodies and lactate) are key substrates used by developing brain for energy, neurotransmitter and lipid biosynthesis, a continuous supply of glucose is critical for the developing brain. There is also an interesting reciprocal relationship between brain energy status and the synthesis of kynurenic acid, an endogenous neuromodulator at excitatory synapses. Thus, mice lacking a major biosynthetic enzyme of kynurenic acid, KAT II, show impaired glucose and lactate metabolism and increased susceptibility to excitotoxic damage in developing brain. The following specific aims will test these hypotheses and provide valuable new information about alterations in brain metabolism, mitochondrial function and neuronal/glial interactions subsequent to injury in developing brain. 1. Determine the consequences of chronic overproduction of lactate on the disposition of lactate in the brain of KAT II knockout mice; 2. Use labeled substrates to determine metabolism, neuronal/glial trafficking and neurotransmitter synthesis by ex vivo 13C-NMR spectroscopy in hypoglycemic, hypoxic/ischemic and KAT II knockout mouse brain; 3. Determine acute changes in the functional metabolism of brain mitochondria after hypoglycemic or hypoxic/ischemic injury; and 4. Test the ability of the neuroprotective compound acetyI-L-carnitine to ameliorate the metabolic alterations in hypoxic/ischemic brain. The information obtained from these studies, together with other segments of the Program Project, will provide new insights into the mechanisms of damage in the immature brain and will aid in the development of neuroprotective strategies.