UREA CYCLE ENZYMOPATHIES

尿素循环酶病

• 批准号: 3311488
• 负责人: SAUL W BRUSILOW
• 金额: $ 21.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-02-01 至 1991-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3311488
• 关键词: Reye's syndrome; aminoacid metabolism; arginase; arginine; argininemia; arginosuccinate lyase deficiency; arginosuccinate synthetase deficiency; benzoates; carbamoyl phosphate synthetase deficiency; carbamoylphosphate synthase; child (0-11); child psychology; citrulline; developmental nutrition; diet therapy; essential aminoacid; genetic disorder diagnosis; glutamine; high performance liquid chromatography; human subject; inborn urea cycle disorder; mass screening; metabolism disorder chemotherapy; newborn human (0-6 weeks); nitrogen metabolism; nutrition related tag; ornithine; ornithine carbamoyltransferase; patient monitoring device; phenylacetates; sex linked trait; urinalysis

The overall objective of this proposal is to develop better diagnostic and therapeutic measures for the management of patients with inborn errors of urea synthesis. These objectives will be met by a long term clinical evaluation of the outcome of such patients treated by dietary modification supplemented with the investigative new drugs, sodium benzoate and sodium phenylacetate which activate endogenous latent pathways of waste nitrogen synthesis and excretion. Modifications of the current protocol includes a study of phenylbutyrate as a substitute for phenylacetate as well as a study of different dosage schedules of these drugs. The role of the intravenous dosage form of these drugs on the hyperammonemia of Reye's syndrome will also be evaluated. The hypothesis that the increased intracranial pressure accompanying hyperammonemia is caused by osmotic shifts of water induced by intracellular free glutamine will be studied in animal models of hyperammonemia. The reliability of the protein tolerance test in identifying women heterozygous for a mutant ornithine transcarbamylase gene will be evaluated comparing the results of this test done on obligate heterozygotes with normal women. The role of arginine deficiency in the pathogenesis of the skin lesion in kwashiorkor will be examined by studying the effect of dietary arginine. The effect of an arginine free diet in normal man and animals will be studied as well as arginine metabolism in an animal model of ornithine transcarbamylase deficiency-the sparse fur mouse. A study in rats of the dietary determinants of citrullinogenesis in isolated mitochondria and ureagenesis in hepatocytes will be done using a meal feeding technique. The relationship between meal feeding and citrullinogenic and ureagenic capacity will be evaluated as will the time course of urea cycle enzyme adaptive changes. A new analytic method for N-acetylglutamate will be employed to re-evaluate its role in ureagenesis under meal feeding conditions. The role of glucagon in citrullinogenesis and ureagenesis in the meal fed rat will be evaluated. The role of glutamine as the nitrogen donor for citrullinogenesis and ureagenesis will be studied in isolated mitochondria and hepatocytes.

该提案的总体目的是开发更好的诊断和 治疗措施，用于管理先天错误的患者 尿素合成。 这些目标将通过长期临床实现 评估通过饮食改性治疗的此类患者的结果 补充了调查性新药，苯甲酸钠和钠 激活废物氮的内源性潜在途径的苯基乙酸酯 合成和排泄。 当前协议的修改包括 苯丁酸苯丁酯作为苯乙酸酯和A的替代品的研究 这些药物的不同剂量时间表的研究。 这些药物的静脉剂量形式的作用在 还将评估雷耶综合征的高症血症。 假设 伴随高症血症的颅内压增加是 由细胞内游离谷氨酰胺诱导的水的渗透变化引起 将研究在高症血症的动物模型中。 蛋白质耐受性测试在识别女性方面的可靠性 将评估突变鸟嘌呤经氨基酰基酶基因的杂合子 比较该测试对强制性杂合子进行的测试的结果 正常妇女。 精氨酸缺乏在皮肤病变发病机理中的作用 将通过研究饮食精氨酸的作用来检查skwashiorkor。 普通人和动物的无精氨酸饮食的影响是 在鸟氨酸的动物模型中研究和精氨酸代谢 经氨基甲基酶缺乏 - 稀疏的皮草小鼠。 一项研究在 肝细胞中的孤立线粒体和尿素发生将使用 进餐技术。 进餐和喂食之间的关系 将评估柑橘氨基氨基蛋白原和尿素能力 尿素周期酶的过程自适应变化。 一种新的分析方法 N-乙酰谷氨酸将被用来重新评估其在尿素中的作用 在进餐条件下。 胰高血糖素在瓜氨基氨基氨基发生中的作用 将评估饮食大鼠的尿素发生。 的作用 谷氨酰胺作为柠檬氨基氨酸发生和尿素发生的氮供体 在孤立的线粒体和肝细胞中进行研究。