Enteral Precursors for Urea Synthesis in Humans

描述(申请人提供)：该研究的长期目标是进一步了解氮流对人体尿素合成的调节。特别关注的是患有尿素周期遗传性疾病(UCDs)的患者。目前资助的研究表明，鸟氨酸转氨甲基酶和精氨基琥珀酸合成酶缺乏症杂合子患者利用谷氨酰胺作为尿素合成的氮源的能力似乎受到部分阻碍，他们依赖肝脏清除肠道中产生的氨来维持餐后氮平衡。初步结果表明，苯丁酸钠是UCDS的一种常见治疗方法，它会扰乱支链氨基酸的代谢。因此，我们认为由于亮氨酸对蛋白质代谢调节的重要性，用丁酸苯酯处理不仅转移了尿素合成中的氮，而且损害了体内蛋白质周转的调节。我们假设：假设1：在治疗水平给予丁酸苯酯，特别是将支链氨基氮转移到谷氨酰胺生产上，而不是组织蛋白质的净合成。假设2：丁酸苯酯治疗因此抑制了身体维持氮平衡的能力，特别是在治疗UCDs和其他代谢性疾病时使用的有限蛋白质摄入量；假设3：同时使用苯丁酸酯和低蛋白饮食治疗UCDs的患者将受益于饮食中支链氨基酸的补充。为了验证这些假设，我们将在正常受试者和尿素合成部分或完全缺陷的个人的研究中使用亮氨酸、谷氨酰胺、苯丙氨酸和尿素代谢的稳定同位素示踪剂。具体目标是：具体目标1：在对照受试者和UCDs杂合子携带者中，确定丁酸苯酯对尿素、谷氨酰胺和支链氨基酸代谢的影响。量化其对体内蛋白质周转的影响。具体目标2：量化尿素循环活性为零的患者的全身蛋白质周转和平衡，这些患者正在接受传统的丁酸苯酯和低蛋白饮食方案。具体目标3：确定口服支链氨基酸补充剂对尿素周期患者和服用丁酸苯酯的对照组蛋白质、亮氨酸和谷氨酰胺代谢的影响。因此，主要目的是利用新的临床导向信息来调节人体氮平衡，开发治疗UCDS和其他代谢性疾病的新的营养方法。此外，预计这一结果将有利于其他蛋白质代谢受损的人。

DESCRIPTION (provided by applicant): The long term goal of the research is to further understand the regulation of nitrogen flow to urea synthesis in humans. A specific focus is on patients with genetic disorders of the urea cycle (UCDs). Currently funded research has shown that inviduals who are heterozygotic for ornithine transcarbamylase and arginino succinic acid synthase deficiency appear to have a partial block in their ability to use glutamine as a nitrogen source for urea synthesis, and that they rely on the hepatic clearance of ammonia generated in the gut to maintain their post prandial N homeostasis. Preliminary results suggest that the administration of sodium phenyl butyrate, a common treatment for UCDs, disrupts branched chain amino acid metabolism. We argue therefore that because of the importance of leucine to protein metabolic regulation, treatment with phenyl butyrate not only diverts N away from urea synthesis, but compromises the regulation of body protein turnover. We hypothesize: Hypothesis 1: Phenyl butyrate, given at therapeutic levels, specifically diverts branched chain amino nitrogen towards glutamine production and away from net tissue protein synthesis. Hypothesis 2: Phenyl butyrate treatment thus inhibits the ability of the body to maintain nitrogen equilibrium, particularly at the restricted protein intakes used in the treatment of UCDs and other metabolic diseases; Hypothesis 3: Patients with UCDs, who are concurrently treated with phenylbutyrate and a low protein diet, will benefit from dietary supplements of branched chain amino acids.To test these hypotheses, we will use stable isotopic tracers of leucine, glutamine, phenylalanine and urea metabolism in studies in normal subjects and individuals with partial or complete defects in urea synthesis. The specific aims will be: Specific aim 1: Determine, in control subjects and heterozygotic carriers of UCDs, the effect of phenyl butyrate on urea, glutamine and branched chain amino acid metabolism. Quantify its effects on body protein turnover. Specific aim 2: Quantify whole body protein turnover and balance in patents with null urea cycle activity who are receiving the conventional regime of phenyl butyrate and a low protein diet. Specific aim 3: Determine the effect of oral branched chain-amino acid supplements on protein, leucine and glutamine metabolism in urea-cycle patients and controls who are receiving phenyl butyrate.The main objective therefore is to use the new clinically oriented information on the regulation of human nitrogen homeostasis, to develop novel nutritional approaches to the treatment of UCDs and other metabolic diseases. In addition it is anticipated that the results will benef it other individuals who have compromised protein metabolism.