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

• 批准号: 7184300
• 负责人: MARY C MCKENNA
• 金额: $ 31.58万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7184300
• 关键词: Krebs' cycle; aminoacid biosynthesis; aspartate; astrocytes; brain metabolism; developmental neurobiology; disease /disorder model; enzyme activity; fatty acid biosynthesis; gamma aminobutyrate; glucose metabolism; glutamate dehydrogenase; glutamine; granule cell; human tissue; intracellular transport; laboratory mouse; lactate dehydrogenases; lactates; malates; neurotransmitter biosynthesis; nuclear magnetic resonance spectroscopy; phenylketonurias

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的研究解决了以下假设：侮辱脑中葡萄糖的供应或代谢，将导致能量代谢，神经/神经胶质代谢运输和神经递质生物合成的急性损害，并可能导致长期损害发育脑发育的大脑。与缺氧/缺血，低血糖发作和某些天生错误有关的神经细胞死亡可能部分归因于代谢的长期改变，即使最初的侮辱停止了，这会导致持续的细胞损害。最近的临床研究 发现儿童复发性降血糖发作会导致轻度至严重的学习障碍。迟钝或早期死亡与损害葡萄糖的氧化代谢或防止丙酮酸在大脑中的葡萄糖代谢中使用丙酮酸的氧化代谢有关。我们还将解决以下假设：对于大脑保持乳酸的适当平衡和利用至关重要，因为这种单羧酸是发展大脑的底物，这可能是成人大脑中神经元的底物。升高的脑乳酸是导致智力低下的许多疾病中的重要特征，并且与较差有关 神经发育结果高危婴儿。尽管单羧酸（酮体和乳酸）是开发大脑以进行能量，神经递质和脂质生物合成的关键底物，但葡萄糖的连续供应对发育中的大脑至关重要。脑能量状态与抗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kat酸kat II的主要生物合成酶的小鼠显示出葡萄糖和乳酸代谢受损，并且增加了发育中大脑中兴奋性毒性损伤的敏感性。以下具体目的将检验这些假设，并提供有关大脑损伤后发生的脑部代谢，线粒体功能和神经元/神经胶质相互作用的变化的宝贵新信息。 1。确定乳酸慢性产生对乳酸在Kat II基因敲除小鼠大脑中的处置的后果； 2。使用标记的底物来确定降血糖，低氧/缺血性和KAT II敲除小鼠脑的代谢，神经元/神经胶质运输和神经递质合成的合成； 3。 确定低血糖或低氧/缺血性损伤后脑线粒体功能代谢的急性变化； 4。测试神经保护性化合物乙酰甲烷胺可以改善低氧/缺血性脑的代谢改变的能力。从这些研究获得的信息以及该计划项目的其他部分将提供有关未成熟大脑损害机制的新见解，并将有助于发展神经保护策略。