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.
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