CHARACTERIZATION OF OMEGA HYDROXYLASE P450 GENE FAMILY

OMEGA 羟化酶 P450 基因家族的表征

• 批准号: 3243832
• 负责人: James Paul Hardwick
• 金额: $ 13.96万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-06-01 至 1995-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3243832
• 关键词: DNA binding protein; DNA footprinting; antibody formation; cytochrome P450; eicosanoid metabolism; enzyme activity; enzyme complex; enzyme induction /repression; enzyme mechanism; enzyme structure; enzyme substrate; gene expression; genetic enhancer element; genetic transcription; human tissue; immunocytochemistry; in situ hybridization; isozymes; laboratory rat; monoclonal antibody; omega 3 fatty acid; oxygenases; restriction fragment length polymorphism; transfection; tumor promoters

The long term objective of this research is to determine the health related effects of induction of the Omega fatty acid hydroxylase gene family (P4501V) by hypolipidemic non-genotoxic tumor promoters. The metabolism of fatty acids, cholesterol and eicosanoids, mediators of paracrine and cellular regulation, by P45OIV members suggest that the regulation of this family may be of importance in inborn errors of fatty acid metabolism, hypercholesteremia, and the inflammation process. The present objective of this grant is to (1) define the size and complexity of the human omega fatty acid hydroxylase P-450 gene family (P4501V), (2) determine the substrate specificities of each P-450 member and whether selective isozymes and activities are polymorphic in the human population, and (3) to define and characterize those genetic elements which function in the expression of these genes and are responsive to induction by tumor promoting hypolipideamic drugs, peroxisomal proliferating agents as well as during starvation and diabetes. Data from these studies will provide insight into the mechanisms of transcriptional activation of omega fatty acid metabolizing P4501V gene family by hypolipideamic drugs, as well as during starvation, and drug induced diabetes. Characterization of the substrate catalytic activities of human P4501V gene will help to determine their function in the omega oxidation of fatty acids, prostaglandins and leukotrines. These data will identify the functional roles these P-450s play in fatty acid cholesterol and eicosanoid metabolism. Results may also have their importance in the human population with respect to inborn errors of fatty acid metabolism, the inflammatory response and their functional role during tumor promotion by non-genotoxic peroxisomal proliferating agents.

这项研究的长期目标是确定健康状况 Omega脂肪酸羟化酶基因诱导的相关影响 家族（P4501V）由降血脂非基因毒性肿瘤促进剂引起。这 脂肪酸、胆固醇和类二十烷酸的代谢， P45OIV 成员的旁分泌和细胞调节表明 该家族的调节可能在肥胖先天性疾病中发挥重要作用 酸代谢、高胆固醇血症和炎症过程。 这笔赠款的当前目标是 (1) 确定规模和 人类欧米伽脂肪酸羟化酶 P-450 基因家族的复杂性 (P4501V), (2) 确定每个 P-450 成员的底物特异性 以及选择性同工酶和活性在人类中是否具有多态性 种群，以及 (3) 定义和表征这些遗传元素 它在这些基因的表达中发挥作用并对 通过促肿瘤降血脂药物、过氧化物酶体诱导 增殖剂以及饥饿和糖尿病期间。 这些研究的数据将提供对机制的深入了解 omega脂肪酸代谢P4501V基因的转录激活 家庭使用降血脂药物，以及饥饿期间和药物 诱发糖尿病。底物催化活性的表征 人类 P4501V 基因的研究将有助于确定其在 omega 中的功能 脂肪酸、前列腺素和白三烯的氧化。这些数据将 确定这些 P-450 在脂肪酸胆固醇中发挥的功能作用 和类二十烷酸代谢。结果也可能具有重要意义 人类存在先天性脂肪酸代谢缺陷， 炎症反应及其在肿瘤促进过程中的功能作用 通过非基因毒性的过氧化物酶体增殖剂。