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

Br 代谢过程中一元羧酸和氨基酸的相互关系

基本信息

批准号：
7062856
负责人：
MARY C MCKENNA
金额：
$ 30.66万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

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.

项目 III 的研究提出了这样的假设：破坏大脑中葡萄糖的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严重损害，并且还可能对发育中的大脑造成长期损害。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归因于新陈代谢的长期改变，即使在最初的损伤停止后，也会导致持续的细胞损伤。最近的临床研究研究发现，儿童反复发生低血糖会导致轻度至重度学习障碍。发育迟缓或过早死亡与先天性缺陷有关，先天性缺陷会损害葡萄糖的氧化代谢或阻止大脑回补途径中葡萄糖代谢中丙酮酸的使用。我们还将讨论这样一个假设，即大脑维持乳酸产生和利用的适当平衡至关重要，因为这种一元羧酸是大脑发育的底物，可能是成人大脑中神经元的底物。脑乳酸升高是许多导致智力低下的疾病的一个突出特征，并且与智力低下有关。神经发育结果高危婴儿。虽然一元羧酸（酮体和乳酸）是发育中的大脑用于能量、神经递质和脂质生物合成的关键底物，但持续供应葡萄糖对于发育中的大脑至关重要。大脑能量状态与犬尿酸（兴奋性突触的内源性神经调节剂）的合成之间也存在有趣的相互关系。因此，缺乏犬尿酸主要生物合成酶 KAT II 的小鼠表现出葡萄糖和乳酸代谢受损，并且在发育中的大脑中对兴奋性毒性损伤的敏感性增加。以下具体目标将检验这些假设，并提供有关发育中大脑损伤后大脑代谢、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.确定乳酸长期过量产生对KAT II基因敲除小鼠大脑中乳酸处置的影响； 2. 使用标记底物通过离体 13C-NMR 波谱测定低血糖、缺氧/缺血和 KAT II 敲除小鼠大脑中的代谢、神经元/神经胶质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； 4.测试神经保护化合物乙酰基-L-肉碱改善缺氧/缺血脑代谢改变的能力。从这些研究中获得的信息以及该计划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制定。