BRANCH CHAIN AMINO ACIDS AND REGULATION OF BODY PROTEIN TURNOVER

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这项建议的总体目标是更深入地了解人体体内的氮代谢，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。我们过去的工作表明，与正常人相比，尿素合成基因缺陷的患者利用葡萄糖胺作为尿素氮源的能力可能会部分受阻。因此，它们更多地依赖肠道生成的氮作为尿素的来源。此外，我们和其他人还表明，对于这类患者，一种常见的治疗方法(即摄入苯丁酸酯或苯乙酸酯，通常与苯甲酸酯联合使用)将尿素合成中的氮转移到替代排泄途径(从而达到其治疗目的)。然而，我们的研究表明，这种治疗方式对支链氨基酸代谢(BCAA)有重大影响。事实上，这种代谢紊乱导致支链氨基酸浓度显著下降，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。独特的是，这种临床情景可能提供一个机会，选择性地评估支链氨基酸在调节全球蛋白质合成中的作用。因此，我们建议在正常受试者和患有尿素合成部分和/或严重缺陷的患者中进行实验，以验证这些假设。这些发现将直接影响我们对这些疾病和其他疾病的营养管理，在这些疾病中，限制蛋白质摄入是主要的治疗手段。

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. Our past work has indicated that in comparison with normal individuals, patients with genetic defects in urea synthesis may exhibit a partial block in their ability to utilize gluatmine as a urea nitrogen source. As a consequence they rely more on enterally generated nitrogen as a source of urea. In addition we and others have also shown that a common therapy for such patients, (i.e., the ingestions ofeither 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). However,our studies suggest that this therapeutic modality has a substantial impact on branched chain amino acid metabolism (BCAA). In fact, this meabolic disruption 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 druge, is to inhibit body protein synthesis. Uniquely,this clinical scenario may provide an opportunity to selectively evaluate the role of branch chain amino acids in regulating global protein synthesis. Accordingly, we propsoe experiments in normal subjects and in patients suffering from partial and/or severe 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 main stay of therapy.