NITROGEN FLUX AND UREAGENESIS IN UREA CYCLE DISORDERS

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。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，制定一项监测尿素循环障碍体细胞基因治疗疗效的方案，并制定改善原发性和继发性尿素生成缺陷诊断的方法。在这些研究中，将使用[15 N-酰胺]谷氨酰胺转化为[15 N]尿素来测量通过尿素循环途径的通量。同时，通过持续输注[18 O][13 C]尿素测量全身尿素通量。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作用，评价蛋白质摄入量和不稳定氮库大小对谷氨酰胺至尿素通量的影响。受试者包括受影响的患者、杂合子家族成员、继发性尿素生成障碍患者和正常志愿者。我们希望这些研究能够更好地诊断和前瞻性管理影响尿素循环的疾病，以及构成新的干预措施，如基因治疗的敏感结果的措施。

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.