MOLECULAR BASIS OF HEPATIC HYPERMETABOLISM IN BURNS

烧伤中肝脏高代谢的分子基础

• 批准号: 2853633
• 负责人: Martin L Yarmush
• 金额: $ 20.05万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2853633
• 关键词: Krebs' cycle; acidity /alkalinity; amination; aminoacid metabolism; aminoacid transport; bioenergetics; burns; carbamoylphosphate synthase; gas chromatography mass spectrometry; glutaminase; intermolecular interaction; intracellular transport; laboratory rat; liver metabolism; molecular dynamics; nitrogen metabolism; nuclear magnetic resonance spectroscopy; oxidation; physical chemical interaction; urea cycle

Profound alterations in the regulation of energy and amino acid metabolism occur after burn injury. Given that the liver plays a major role in regulating whole body amino acid metabolism and is the primary site of nitrogen conversion into urea, we hypothesize that burn injury induces intrinsic metabolic changes in liver, and that these changes are responsible in large part for the aberrant amino acid profile as well as the increased nitrogen loss in the patient after burns. The overall objective of the proposed studies is to investigate, in a well characterized and controlled perfused liver model, the molecular mechanisms which trigger the overall metabolic changes that occur in the liver in response to burn trauma, and how these changes affect the metabolism of conditionally essential amino acids and the conversion of amino acid nitrogen into urea. The specific aims of the proposed work are: 1. To determine the mechanisms of increased amino acid oxidation in burned rat liver. 2. To determine the mechanisms of increased urea production in the burned rat liver and identify critical urea and TCA cycle interactions. The proposed studies will provide basic, quantitative information on the pathways activated by burn injury in liver and on the molecular mechanisms which mediate this activation. This investigation will form a rational basis for (1) the future development of nutritional regimens and therapeutic approaches aimed at reducing the catabolic response to burn injury, and (2) for the investigation of the gene expression component in the modulation of amino acid oxidation.

烧伤后能量和氨基酸代谢的调节发生深刻变化。 鉴于肝脏在调节全身氨基酸代谢中发挥着重要作用，并且是氮转化为尿素的主要场所，我们假设烧伤会引起肝脏的内在代谢变化，而这些变化在很大程度上是造成异常的原因。氨基酸谱以及烧伤后患者氮流失增加。拟议研究的总体目标是在一个良好表征和控制的灌注肝脏模型中调查触发肝脏中响应烧伤而发生的整体代谢变化的分子机制，以及这些变化如何影响有条件的代谢必需氨基酸和氨基酸氮转化为尿素。拟议工作的具体目标是： 1. 确定烧伤大鼠肝脏中氨基酸氧化增加的机制。 2. 确定烧伤大鼠肝脏中尿素产量增加的机制，并确定关键的尿素和 TCA 循环相互作用。拟议的研究将提供有关肝脏烧伤激活的途径以及介导这种激活的分子机制的基本定量信息。 这项研究将为（1）未来开发旨在减少烧伤分解代谢反应的营养方案和治疗方法，以及（2）研究调节氨基酸氧化的基因表达成分奠定合理的基础。