PATHOGENESIS OF HEPATIC COMA

肝昏迷的发病机制

• 批准号: 3225647
• 负责人: Arthur Joseph Cooper
• 金额: $ 28.85万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3225647
• 关键词: 6 phosphofructokinase; acute disease /disorder; alpha ketoglutarate; aminoacid metabolism; aspartate; astrocytes; bioenergetics; brain metabolism; cellular pathology; chronic disease /disorder; enzyme inhibitors; enzyme mechanism; glutamate dehydrogenase; glutathione; hepatic coma /encephalopathy; hepatotoxin; high performance liquid chromatography; laboratory mouse; laboratory rat; liver failure; liver function; malates; medical complication; neurotransmitter metabolism; nitrogen balance; pathologic process; radiotracer; tissue /cell culture; urea cycle

The underlying assumption of the proposed research is that excess ammonia is a major factor in the neurological complications arising from both acute and chronic liver disease. Failure of the diseased liver to remove ammonia from the portal circulation, and limited capacity of extrahepatic tissues to remove this ammonia, leads to an increase in ammonia entering the brain. Our hypothesis is that the increased ammonia load leads to a disruption of cerebral energy metabolism by interfering with, a) the malate-aspartate shuttle (MAS) for the transport of reducing equivalent between cytosol and mitochondria and with b) the TCA cycle (at the level of alpha-ketoglutarate dehydrogenase complex and, possibly, at other dehydrogenase steps). Prolonged exposure to excess ammonia results in increased cerebral "sensitivity" to ammonia, hypoxia, and other superimposed metabolic stresses. Astrocytes in the brains of liver diseased patients and in the brains of animals subjected to experimentally-induced metabolic impairment. To evaluate the role of ammonia in the pathogenesis of hepatic encephalopathy our goals will be multifaceted: 1) to design inhibitors of aspartate aminotransferase (an important component of the MAS) that will cross the blood-brain barrier, in order to investigate the metabolic consequences of disruption of the MAS; 2) to use [13N] leucine, [13N] tyrosine, [13N-amine'- and [13N-amide]glutamine (13N, positron emitter; t 1/2=9.96 min.) to label the astrocytic pool in vivo, to provide evidence that astrocytic glutamine is a precursor of neuronal GABA and to determine whether this pathway is disrupted in the hyperammonemic animal; 3) to elucidate the role of glutathione in the normal and hyperammonemic rat brain; 4) to determine the major source of metabolically-derived ammonia in brain (glutaminase, glutamate dehydrogenase, and/or the purine nucleotide cycle). Finally, some workers have questioned the notion that the major role of the urea cycle is to remove excess nitrogen and have suggested that the urea cycle may have evolved to regulate acid-base levels. To provide evidence for, or against, this theory we will use our recently developed tracer techniques to investigate the short-term metabolic fate of 13N labeled ammonia, alanine and glutamate in the metabolically acidotic rat. The urea cycle is compromised in liver disease. Therefore, it is important to understand how the disruption of this cycle affects both whole-body nitrogen homeostasis and acid-base balance in liver disease. It is hoped that the results of the above mentioned studies will lead to improved therapies in patients with liver disease.

拟议研究的基本假设是 氨是由神经系统并发症的主要因素 急性和慢性肝病。 患病的肝脏失败 从门户流通中去除氨，容量有限 肝外组织去除这种氨，导致增加 氨进入大脑。 我们的假设是增加 氨负荷导致脑能量代谢破坏 干扰，a）苹果酸天冬氨酸班车（MAS） 在细胞质和线粒体和线粒体之间还原等效的运输 与b）TCA循环（在α-酮戊二酸脱氢酶的水平下 复杂的，可能在其他脱氢酶步骤）。 长时间 暴露于氨过量会导致脑“敏感性”提高 氨，缺氧和其他叠加的代谢应激。 肝病患者大脑中的星形胶质细胞和大脑 受到实验诱导的代谢损害的动物。 到 评估氨在肝发病机理中的作用 脑病我们的目标将是多方面的：1）设计抑制剂 天冬氨酸氨基转移酶（MAS的重要组成部分） 将越过血脑屏障，以调查 MAS中断的代谢后果； 2）使用[13n] 亮氨酸，[13n]酪氨酸，[13n-amine'-和[13n-酰胺]谷氨酰胺（13n，，， 正面发射器； t 1/2 = 9.96分钟。）在体内标记星形胶质细胞池， 为了证明星形细胞谷氨酰胺是神经元的前体 GABA并确定该途径是否在 高症动物； 3）阐明谷胱甘肽在 正常和高症大鼠脑； 4）确定主要来源 大脑中代谢衍生的氨（谷氨酰胺酶，谷氨酸 脱氢酶和/或嘌呤核苷酸周期）。 最后，有些 工人质疑尿素周期的主要作用的观念 是去除多余的氮，并建议尿素周期 已经演变为调节酸碱水​​平。 提供证据或 反对，我们将使用我们最近开发的示踪剂 研究标记为13N的短期代谢命运的技术 代谢性酸性大鼠中的氨，丙氨酸和谷氨酸。 这 尿素周期在肝病中受到损害。 因此，这很重要 了解该周期的破坏如何影响全身 肝病中的氮稳态和酸碱平衡。 这是 希望上述研究的结果将导致 改善肝病患者的疗法。