NITROGEN FLUX AND UREAGENESIS IN UREA CYCLE DISORDERS

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。 正常受试者和尿素循环障碍家庭的成员，包括半合子OTC缺陷男性(轻度和重度)、杂合子OTC缺陷女性、常染色体隐性尿素循环缺陷患者(瓜氨酸血症、精氨酸尿症、精氨酸血症)、他们的父母和他们的同胞将在CRC中进行研究，以评估[15N-酰胺]谷氨酰胺到[15N]尿素的转化。这将与注入[18O][13C]尿素测量的总尿素产量进行比较。选定的受试者将在相同的条件下进行两次研究，以确定测量的可变性。代谢转换将与基因和表型相关。 受试者将在增加和减少氮摄入量的条件下进行研究，以评估蛋白质负荷和不稳定氮池的大小对从谷氨酰胺到尿素的流量测量的影响。正常受试者也将被研究精氨酸和替代途径药物的给药和不给药。 C.有症状和无症状的尿素循环患者将通过氮通量进行评估，他们的尿素循环活性指数由15N从谷氨酰胺到尿素的比例转移([15N]尿素/[15N]谷氨酰胺)将与表型严重程度相关。通过1)家族史、2)血氨和氨基酸、3)尿口酸尿、4)酶分析和/或5)DNA突变分析的组合来确定他们的15N指数是否与这些表型严重程度的其他指标相关联，将对尿素循环的高危患者进行研究。最后，将对患有分子或生物化学定义的线粒体疾病的受试者进行研究，以确定线粒体异常是否影响尿失禁。

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. A. Normal subjects and members of families with urea cycle disorders including hemizygous OTC deficient males (mild and severe), heterozygous OTC deficient females, affected patients with autosomal recessive urea cycle defects (citrullinemia, argininosuccinic aciduria, argininemia), their unaffected parents, and their sibs will be studied in the CRC to evaluate conversion of [15N-amide]glutamine to [15N]urea. This will be compared to total urea production measured with infusion of [18O][13C]urea. Selected subjects will be studied twice under identical conditions to determine the variability of the measurements. Metabolic conversion will be correlated with the genotype and phenotype. B. Subjects will be studied under conditions of increased and decreased nitrogen intake to assess the effects of protein load and the size of the labile nitrogen pool on the measurement of flux from glutamine to urea. Normal subjects will also be studied with and without administration of arginine and alternative pathway drugs. C. Urea cycle patients, both symptomatic and asymptomatic, will be evaluated by nitrogen flux and their index of urea cycle activity defined by proportion transfer of 15N from glutamine to urea ([15N]urea/[15N]glutamine)will be correlated with phenotypic severity. At-risk urea cycle patients defined by combinations of either 1) family history, 2) plasma ammonia and amino acids, 3) urine orotic aciduria, 4) enzymatic analysis, and/or 5) DNA mutation analysis will be studied to determine whether their 15N index correlates with these other measures of phenotypic severity. Finally, subjects with molecularly or biochemically defined mitochondrial disorders will be studied for their baseline rates of ureagenesis on a low protein diet to determine whether mitochondrial abnormalities affect ureagenesis.