Enteral Precursors for Urea Synthesis in Humans

描述（由申请人提供）：本研究的长期目标是进一步了解人体氮流对尿素合成的调节。特别关注的是尿素循环遗传疾病（UCDs）患者。目前资助的研究表明，鸟氨酸转氨基甲酰基酶和精氨酸琥珀酸合酶缺乏症的杂合子个体似乎部分阻断了利用谷氨酰胺作为尿素合成氮源的能力，并且他们依赖于肠道中产生的氨的肝脏清除来维持餐后氮稳态。初步结果表明，丁酸苯钠是UCDs的一种常用治疗方法，可破坏支链氨基酸代谢。因此，我们认为，由于亮氨酸对蛋白质代谢调节的重要性，丁酸苯酯处理不仅使氮从尿素合成中转移，而且损害了对身体蛋白质代谢的调节。我们的假设是：假设1：丁酸苯在治疗水平上，特别地将支链氨基氮转移到谷氨酰胺的生产中，而远离净组织蛋白质的合成。假设2：因此，丁酸苯酯治疗抑制了身体维持氮平衡的能力，特别是在治疗UCDs和其他代谢疾病时限制蛋白质摄入的情况下；假设3:ucd患者同时服用苯基丁酸盐和低蛋白饮食，将受益于支链氨基酸的膳食补充。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体中使用亮氨酸、谷氨酰胺、苯丙氨酸和尿素代谢的稳定同位素示踪剂。具体目的如下：目的1：确定对照和UCDs杂合子携带者丁酸苯酯对尿素、谷氨酰胺和支链氨基酸代谢的影响。量化其对人体蛋白质周转的影响。具体目标2：量化尿素循环活性为零的接受常规丁酸苯和低蛋白质饮食的专利的全身蛋白质周转和平衡。具体目的3：确定口服支链氨基酸补充剂对尿素循环患者和接受丁酸苯治疗的对照组中蛋白质、亮氨酸和谷氨酰胺代谢的影响。因此，主要目标是利用有关人体氮稳态调节的新的临床导向信息，开发新的营养方法来治疗UCDs和其他代谢疾病。此外，预计该结果将使其他蛋白质代谢受损的个体受益。

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.