Abstract

The goal of the research is to achieve a deeper understanding of in vivo nitrogen metabolism in patients with urea cycle disorders. Recent stable isotope-based studies of urea synthesis in normal individuals and in carriers of ornithine transcarbamylase deficiency (OTCD) have led us to the following hypotheses. 1: Urea precursors derived from the first- pass intestinal metabolism of dietary protein are utilized more efficiently for ureagenesis than are precursors derived from tissue metabolism. 2: As a consequence, individuals who have a compromised urea cycle activity are able to metabolize excessive dietary protein more effectively than peripherally generated precursors. This underlies the observation that the imposition of stress or infection is associated with metabolic decompensation in female OTCD carriers and mildly affected OTCD males. 3: The difference in the efficiency with which urea is synthesized from substrates of intestinal and peripheral origin is an important factor in the variable phenotype and episodic nature of OTCD. These hypotheses will be tested by carrying out stable isotopic studies of urea synthesis in normal controls and OTCD carriers. The studies will have the following specific aims. 1: Quantify urea synthesis from dietary and systemic urea nitrogen precursors in the prandial state. 2: Quantify the impact of a more prolonged period of moderate or higher protein intake on the relative utilization of endogenous and dietary nitrogen sources for ureagenesis. Urea production will be determined with [18O] urea and will be compared with simultaneous measurements of the transfer of [15N] from oral 15NH4CI, or [15N] alanine (as dietary tracers) or from intravenous 15NH4CI, [5-15N] glutamine or [15N]alanine (as tracers of endogenously generated precursors). The information will enhance understanding of nitrogen metabolism in OTCD and may lead to improvements in nutritional care by establishing the range of protein intakes to which patients can successfully adapt. In addition the results will be of broader significance to understanding nitrogen metabolism and ureagenesis during stress and infection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054450-02
Application #
2906288
Study Section
Nutrition Study Section (NTN)
Program Officer
Mckeon, Catherine T
Project Start
1998-09-30
Project End
2002-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Nagamani, Sandesh C S; Erez, Ayelet; Lee, Brendan (2012) Argininosuccinate lyase deficiency. Genet Med 14:501-7
Nagamani, Sandesh C S; Shchelochkov, Oleg A; Mullins, Mary A et al. (2012) A randomized controlled trial to evaluate the effects of high-dose versus low-dose of arginine therapy on hepatic function tests in argininosuccinic aciduria. Mol Genet Metab 107:315-21
Nagamani, Sandesh C S; Campeau, Philippe M; Shchelochkov, Oleg A et al. (2012) Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. Am J Hum Genet 90:836-46
Nagamani, Sandesh C S; Lee, Brendan; Erez, Ayelet (2012) Optimizing therapy for argininosuccinic aciduria. Mol Genet Metab 107:10-4
Marini, Juan C; Lanpher, Brendan C; Scaglia, Fernando et al. (2011) Phenylbutyrate improves nitrogen disposal via an alternative pathway without eliciting an increase in protein breakdown and catabolism in control and ornithine transcarbamylase-deficient patients. Am J Clin Nutr 93:1248-54
Erez, Ayelet; Nagamani, Sandesh C Sreenath; Lee, Brendan (2011) Argininosuccinate lyase deficiency-argininosuccinic aciduria and beyond. Am J Med Genet C Semin Med Genet 157C:45-53
Brunetti-Pierri, Nicola; Lanpher, Brendan; Erez, Ayelet et al. (2011) Phenylbutyrate therapy for maple syrup urine disease. Hum Mol Genet 20:631-40
Erez, Ayelet; Nagamani, Sandesh C S; Shchelochkov, Oleg A et al. (2011) Requirement of argininosuccinate lyase for systemic nitric oxide production. Nat Med 17:1619-26
Lee, Brendan; Rhead, William; Diaz, George A et al. (2010) Phase 2 comparison of a novel ammonia scavenging agent with sodium phenylbutyrate in patients with urea cycle disorders: safety, pharmacokinetics and ammonia control. Mol Genet Metab 100:221-8
Marini, Juan C; Didelija, Inka Cajo; Castillo, Leticia et al. (2010) Glutamine: precursor or nitrogen donor for citrulline synthesis? Am J Physiol Endocrinol Metab 299:E69-79

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