BRANCH CHAIN AMINO ACIDS AND REGULATION OF BODY PROTEIN TURNOVER

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 本提案的总体目标是实现对人体体内氮代谢的更深入了解，具体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。 因此，它们更依赖于肠内产生的氮作为尿素的来源。此外，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，通常与苯甲酸盐组合）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）。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，尽管总蛋白摄入量足够。这些药物作用的一个预测结果是抑制体内蛋白质合成。独特的是，这种临床情况可能提供了一个机会，选择性地评估分支链氨基酸在调节全球蛋白质合成的作用。因此，我们建议在正常受试者和患有部分和/或严重尿素合成缺陷的患者中进行实验来验证这些假设。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。

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.