BRANCH CHAIN AMINO ACIDS AND REGULATION OF BODY PROTEIN TURNOVER

支链氨基酸和身体蛋白质周转的调节

• 批准号: 7374933
• 负责人: Brendan Lee
• 金额: $ 6.11万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7374933
• 关键词: BRANCH; CHAIN; AMINO; ACIDS; REGULATION

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goal of this proposal is to achieve a deeper understanding of in vivo nitrogen metabolism in human, with specific foci on interactions between essential amino acid metabolism and urea synthesis and on diseases affecting the urea cycle, and branched chain amino acid metabolism in Maple Syrup Urine Disease (MSUD). Patients with genetic defects affecting urea synthesis may exhibit a partial block in their ability to utilize glutamine as a urea nitrogen source1. We and others have also shown that a common therapy for such patients, (i.e., the ingestion of either phenylbutyrate or phenylacetate, often in combination with benzoate) diverts nitrogen from the urea synthesis to alternative routes of excretion (and hence achieves its therapeutic objective). Our studies suggest that this therapy has a substantial impact on branched chain amino acid metabolism (BCAA). This leads to a marked fall in BCAA concentrations in spite of adequate levels of total protein intake. One predicted outcome of the effect of these drugs is to inhibit body protein synthesis. The effect of buphenyl on branched chain amino acid metabolism may also affect the treatment of Maple Syrup Urine Disease (MSUD). MSUD is an inherited metabolic disorder which affects the metabolism of the three branched chain amino acids (BCAA) leucine, isoleucine and valine. MSUD patients have elevated branched chain amino acids and the branched chain keto acids due to a defect in the enzyme complex branched chain keto acid dehydrogenase (BCKD). It is these elevations that cause a patient with MSUD to be symptomatic. Our past work indicates that phenylbutyrate decreases BCAA and branched chain keto acids in control subjects and patients with urea cycle disorders. If this effect is also found in patients with MSUD, it may be clinically relevant as phenylbutyrate may be given therapeutically to decrease BCAA levels and their byproducts in these patients. Accordingly, we propose experiments in normal subjects and in patients suffering from partial and/or severe defects in urea synthesis, MSUD patients, as well as disorders leading to secondary defects in urea synthesis, to test these hypotheses. These findings should directly impact on our nutritional management of these and other disorders in which restriction of protein intake is a mainstay of therapy.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。本提案的总体目标是更深入地了解人体体内氮代谢，特别关注必需氨基酸代谢和尿素合成之间的相互作用，以及影响尿素循环的疾病，以及枫树糖尿病尿病（MSUD）中的支链氨基酸代谢。具有影响尿素合成的遗传缺陷的患者可能表现出部分阻断其利用谷氨酰胺作为尿素氮源的能力1。我们和其他人还表明，对这类患者的一种常见疗法，（即，苯丁酸盐或苯乙酸盐的摄入，通常与苯甲酸盐结合）将氮从尿素合成转移到替代的排泄途径（并因此实现其治疗目的）。我们的研究表明，这种疗法对支链氨基酸代谢（BCAA）有重大影响。这导致BCAA浓度显着下降，尽管总蛋白质摄入量充足。这些药物作用的一个预测结果是抑制身体蛋白质合成。丁苯对支链氨基酸代谢的影响也可能影响枫尿病（MSUD）的治疗。MSUD是一种遗传性代谢紊乱，其影响三种支链氨基酸（BCAA）亮氨酸、异亮氨酸和缬氨酸的代谢。由于酶复合物支链酮酸脱氢酶（BCKD）的缺陷，MSUD患者具有升高的支链氨基酸和支链酮酸。正是这些升高导致MSUD患者出现症状。我们过去的工作表明，苯丁酸盐减少BCAA和支链酮酸在对照组和尿素循环障碍患者。如果在MSUD患者中也发现这种效应，则可能具有临床相关性，因为可以给予苯丁酸酯治疗以降低这些患者的BCAA水平及其副产物。因此，我们提出了在正常受试者和患有部分和/或严重缺陷的尿素合成，MSUD患者，以及导致继发性缺陷的尿素合成障碍的患者中进行实验，以测试这些假设。这些发现应该直接影响我们对这些疾病和其他疾病的营养管理，其中限制蛋白质摄入是治疗的主要手段。