NITROGEN FLUX AND UREAGENESIS IN UREA CYCLE DISORDERS

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 研究中心，而研究中心不一定是研究者所在的机构。 A.将在CRC中研究正常受试者和尿素循环障碍家族成员，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（瓜氨酸血症、氨基琥珀酸尿症、精氨酸血症）受累患者、其未受影响的父母及其同胞，以评价[15 N-酰胺]谷氨酰胺向[15 N]尿素的转化。 这将与输注[18 O][13 C]尿素测量的总尿素产量进行比较。 将在相同条件下对选定受试者进行两次研究，以确定测量值的变异性。 代谢转换将与基因型和表型相关。 B。将在增加和减少氮摄入量的条件下对受试者进行研究，以评估蛋白质负荷和不稳定氮库的大小对谷氨酰胺至尿素通量测量的影响。 正常受试者也将在给予和不给予精氨酸和旁路途径药物的情况下进行研究。 C.将通过氮通量评价尿素循环患者（包括有症状和无症状），并将其尿素循环活性指数（由15 N从谷氨酰胺转移至尿素的比例（[15 N]尿素/[15 N]谷氨酰胺）定义）与表型严重程度相关。 将研究通过1）家族史、2）血浆氨和氨基酸、3）尿乳清酸尿症、4）酶分析和/或5）DNA突变分析的组合定义的尿素循环风险患者，以确定其15 N指数是否与表型严重程度的这些其他指标相关。 最后，将研究患有分子或生化定义的线粒体疾病的受试者在低蛋白饮食下的尿素生成基线率，以确定线粒体异常是否影响尿素生成。

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.