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

项目III中的研究提出了一个假设，即破坏大脑中葡萄糖供应或代谢的损伤将导致能量代谢、神经元/神经胶质代谢运输和神经递质生物合成的急性损伤，还可能导致发育中的大脑的长期损伤。与缺氧/缺血、低血糖发作和一些先天性缺陷相关的神经细胞死亡可能部分是由于代谢的长期改变，即使在最初的损伤停止后也会导致持续的细胞损伤。近期临床研究 已经发现儿童反复出现的低血糖会导致轻度到重度的学习障碍。发育迟缓或早死与先天性缺陷有关，这些先天性缺陷损害葡萄糖的氧化代谢或阻止在大脑回补途径中利用葡萄糖代谢中的丙酮酸。我们还将解决的假设，这是至关重要的大脑保持适当的平衡的生产和利用乳酸，因为这种一元羧酸是一个基板发育的大脑，可能是神经元在成人大脑。脑乳酸盐升高是导致智力迟钝的许多疾病的突出特征，并且与不良的 神经发育结果高危婴儿。虽然一元羧酸（酮体和乳酸盐）是发育中的大脑用于能量、神经递质和脂质生物合成的关键底物，但葡萄糖的持续供应对发育中的大脑至关重要。脑能量状态和犬尿烯酸（兴奋性突触的内源性神经调质）的合成之间也存在有趣的相互关系。因此，缺乏犬尿烯酸的主要生物合成酶KAT II的小鼠显示出葡萄糖和乳酸代谢受损，并且在发育中的大脑中对兴奋性毒性损伤的易感性增加。以下具体目标将测试这些假设，并提供有价值的新信息，脑代谢的变化，线粒体功能和神经元/神经胶质细胞的相互作用损伤后，在发育中的大脑。1.确定慢性乳酸过量产生对KAT II基因敲除小鼠脑中乳酸处置的后果; 2.使用标记的底物通过离体13 C-NMR光谱测定低血糖、缺氧/缺血和KAT II敲除小鼠脑中的代谢、神经元/神经胶质细胞运输和神经递质合成; 3. 确定低血糖或缺氧/缺血损伤后脑线粒体功能代谢的急性变化;和4.测试神经保护化合物乙酰-L-肉毒碱改善缺氧/缺血脑中代谢改变的能力。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，并将有助于神经保护策略的发展。

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.