Enteral Precursors for Urea Synthesis in Humans

人体尿素合成的肠内前体

• 批准号: 6931860
• 负责人: Brendan Lee
• 金额: $ 24.1万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931860
• 关键词: aminoacid biosynthesis; branched chain aminoacid; clinical research; diet therapy; dietary proteins; glutamates; glutamine; human subject; nitrogen metabolism; nutrition related tag; ornithine carbamoyl phosphate deficiency; patient care management; phenylbutyrates; stable isotope; urea; urea cycle

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.

描述（由申请人提供）：本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。一个具体的重点是对患者的遗传性疾病的尿素循环（UCD）。目前资助的研究表明，对于鸟氨酸转氨甲酰酶和氨基琥珀酸合酶缺乏症的杂合子的无活力者，其使用谷氨酰胺作为尿素合成的氮源的能力似乎部分阻断，并且它们依赖于肝脏清除肠道中产生的氨来维持其餐后N稳态。初步结果表明，苯丁酸钠的管理，一个共同的治疗UCD，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，用丁酸苯酯治疗不仅使N从尿素合成中转移，而且损害了机体蛋白质周转的调节。我们假设：假设1：丁酸苯酯，在治疗水平，具体转向支链氨基氮对谷氨酰胺生产和远离净组织蛋白质合成。假设二：因此，丁酸苯酯治疗抑制了身体维持氮平衡的能力，特别是在用于治疗UCD和其他代谢疾病的限制蛋白质摄入量时;假设3：同时接受苯丁酸盐和低蛋白饮食治疗的UCD患者将受益于支链氨基酸的膳食补充剂。为了验证这些假设，我们将使用亮氨酸的稳定同位素示踪剂，谷氨酰胺、苯丙氨酸和尿素代谢的研究中，在正常受试者和个人的部分或完全缺陷的尿素合成。具体目标是：具体目标1：在对照受试者和UCD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。量化其对身体蛋白质周转的影响。具体目标2：对接受丁酸苯酯常规治疗方案和低蛋白饮食的无尿素循环活性患者的全身蛋白质周转和平衡进行量化。具体目标3：确定口服支链氨基酸补充剂对正在接受丁酸苯酯治疗的尿素循环患者和对照组的蛋白质、亮氨酸和谷氨酰胺代谢的影响。因此，主要目的是利用关于人体氮稳态调节的新临床导向信息，开发治疗UCD和其他代谢性疾病的新营养方法。此外，预计该结果将使其他蛋白质代谢受损的个体受益。