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 goal of our research is to achieve a deeper understanding of in vivo nitrogen metabolism in patients with urea cycle defects and of differences in the bioavailability of enteral vs. systemic sources of nitrogen. We, and others, have argued that stable isotopic investigations of nitrogen metabolism provide the most generally applicable approach to the assessment of the underlying metabolic state of urea cycle patients1, particularly those who have partial enzymatic deficiencies (e.g. heterozygous carriers of ornithine transcarbamylase deficiency (OTCD)). Our preliminary studies have led us to conclude that OTCD carriers and mildly affected hemizygous otcd males have a specific compromise in their ability to transfer the amide-N group of glutamine to urea. In these studies the OTCD carriers had near normal absolute rates of urea synthesis at protein intakes less than 0.8 g/kg/d AND sources of urea nitrogen other than glutamine appear to be of greater quantitative importance to these individuals than they are to normal subjects. In these studies, we propose to measure the relative flux of intestinally vs. systemically delivered 15N nitrogen precursors into [15N]urea. These measures in control subjects and in patients with partial reduction in urea cycle activity will determine whether differences in bioavailability of these different sources may underlie the tendency for such patients to become hyperammonemic during episodes of stress (where peripheral nitrogen mobilization predominates) vs. instances of increased protein intake (where enteral sources predominate). Ultimately, such studies may provide insight into the differences of enteral vs. parental sources of nutrition in critically ill states involving for example liver failure.
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