NITROGEN FLUX AND UREAGENESIS IN UREA CYCLE DISORDERS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。该项目的总体目标是更好地了解尿素循环障碍患者的氮代谢，制定监测尿素循环障碍的躯体基因治疗疗效的方案，并开发改进尿失禁原发和继发缺陷的诊断方法。在这些研究中，通过尿素循环途径的流量将通过将[15N-酰胺]谷氨酰胺转化为[15N]尿素来测量。同时，通过持续输注[~(18)O][~(13)C]尿素来测量体内总尿素通量。将通过研究不同蛋白质摄入水平的受试者以及研究精氨酸、苯甲酸钠和苯丁酸钠药物的效果来评估蛋白质摄入量和不稳定氮池的大小对从谷氨酰胺到尿素的流量的影响。研究对象将包括受影响的患者、杂合子家庭成员、继发性尿失禁患者和正常志愿者。我们期望这些研究能够对影响尿素循环的疾病进行更好的诊断和前瞻性管理，并为基因治疗等新的干预措施制定敏感的结果衡量标准。

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 goals of this project are to achieve a better understanding of nitrogen metabolism in patients with urea cycle disorders, to develop a protocol for monitoring efficacy of somatic gene therapy for urea cycle disorders, and to develop methods for improving diagnosis of primary and secondary defects of ureagenesis. In these studies flux through the urea cycle pathway will be measured using conversion of [15N-amide]glutamine to [15N]urea. At the same time total body urea flux will be measured by constant infusion of [18O][13C]urea. The effect of protein intake and size of the labile nitrogen pool on flux from glutamine to urea will be evaluated by studying subjects on different levels of protein intake and by studying the effect of arginine, sodium benzoate, and sodium phenylbutyrate medications. Subjects will include affected patients, heterozygous family members, patients with secondary disorders of ureagenesis, and normal volunteers. We expect that these studies will enable better diagnosis and prospective management of disorders affecting the urea cycle, as well as constitute sensitive outcome measures for novel interventions such as gene therapy.