Investigations into the Glutamine-Citruline-Arginine Pathway in Sepsis

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DESCRIPTION (provided by applicant): Dr. Christina Kao is an assistant professor in the Section of Pulmonary, Critical Care, and Sleep Medicine at Baylor College of Medicine (BCM). Her short-term goal is to develop the knowledge and skills to conduct metabolic research using stable isotope methods. Her long-term goal is to become an independent investigator studying nutritional and metabolic aspects of critical illness and lung disease. Dr. Kao is enrolled in the MS track of the Clinical Scientist Training Program at BCM, and she has access to the extensive resources of the Texas Medical Center, including the Children's Nutrition Research Center and a multi-hospital system. Dr. Kao will examine the metabolic relationship between glutamine and arginine. These amino acids are linked by an inter-organ pathway involving intestinal conversion of glutamine to citrulline followed by renal uptake of citrulline and conversion to arginine. She proposes that, in septic patients, (a) alterations in the availability and whole-body and splanchnic metabolism of glutamine will lead to decreased synthesis of citrulline and arginine and (b) glutamine supplementation will elicit an increase in citrulline, and hence arginine, synthesis. Stable isotope tracer methods will be used to test specific aspects of these hypotheses. Specific aim 1 will determine differences in the rate of glutamine conversion to citrulline and the fractional splanchnic extraction of glutamine in septic patients and healthy controls. The hypothesis is that septic patients have decreased citrulline synthesis from glutamine, and that the rate of citrulline production is directly related to the rate of splanchnic extraction of glutamine. Specific aim 2 will determine the rate of de novo arginine synthesis from its precursors, citrulline and glutamine, in septic patients and healthy controls. The hypothesis is that decreased glutamine availability leads to decreased de novo arginine synthesis in septic patients. Specific aim 3 will determine the effects of enteral and parenteral glutamine supplementation on arginine and citrulline synthesis in septic patients. The hypothesis is that glutamine supplementation of septic patients will lead to increased citrulline and de novo arginine synthesis, and the magnitude of this increase will be greater with enteral compared to parenteral supplementation. PUBLIC HEALTH RELEVANCE: Two compounds, arginine and glutamine, help our body fight severe infections. This research will help to better define the relationship between these two compounds and will determine if supplying more of one (glutamine) will in turn lead to increases in the other (arginine). Better understanding of the body's utilization of these two compounds can contribute to improved nutritional therapy in patients with severe infection.