REGULATION OF EXPRESSION OF LONG CHAIN ACYL COA DEHYDROGENASE

线粒体酶在能量产生中起重要作用， 在许多组织中转导，但在中间代谢中是关键， 特别是脂肪酸，在肝脏和肠道。长链酰基 CoA脱氢酶（LCAD）催化β-氧化的第一步 线粒体基质中的长链脂肪酸不足 这种酶最近被认为是引起雷氏综合征的原因， 婴儿猝死和心肌病我们将采用分子和 细胞生物学技术追求以下目标：i） 阐明LCAD基因在肝脏中表达的调节， 肠和其他组织在发展过程中，随着饮食的变化， ii）分析LCAD基因表达的变化 在培养的人类肝脏和肠细胞中， 营养供应;和iii）确定LCAD的分子基础 人类的缺陷。这项建议的具体目标包括： 人和大鼠LCAD CDNAS和人LCAD CDNAS的分离和表征 基因，分析大鼠和人中LCAD mRNA稳态水平 LCAD基因组调控的组织、分离和表征 对饮食变化有反应的元素， 通过晶体学和X射线衍射分析人LCAD蛋白， 分离人LCAD缺陷的突变。 这些研究将增加对基因表达的理解， 调节，特别是当这发生在线粒体蛋白编码 以及改变脂肪酸的影响， 代谢对肝脏和肠道功能，无论是在健康和 病态的国家

Mitochondrial enzymes play essential roles in energy production and transduction in many tissues, but are key in intermediary metabolism, especially of fatty acids, in the liver and intestine. Long chain acyl CoA dehydrogenase (LCAD) catalyzes the first step in the Beta-oxidation of long chain fatty acids in the mitochondrial matrix. Deficiency of this enzyme has recently been recognized to cause Reye's syndrome, sudden infant death, and cardiomyopathy. We will employ molecular and cellular biologic techniques to pursue the following goals: i) elucidation of the regulation of expression of the LCAD gene in liver, intestine and other tissues during development, with variations in diet, and in disease states; ii) analysis of changes in LCAD gene expression in cultured human liver and intestinal cells with alterations in nutrient supply; and iii) determination of the molecular basis of LCAD deficiency in humans. The specific aims of this proposal include the isolation and characterization of human and rat LCAD CDNAS and the human gene, analysis of LCAD MRNA steady state levels in rat and human tissues, isolation and characterization of LCAD genomic regulatory elements responsive to changes in diet, delineation of the structure of human LCAD protein through crystallography and x-ray diffraction, and isolation of the mutations in human LCAD deficiency. These studies will increase understanding of gene expression and regulation, especially as this occurs for mitochondrial proteins encoded on the nuclear genome, and of the effects of altered fatty acid metabolism on liver and intestinal function, both in healthy and diseased states.