Investigations into the Glutamine-Citruline-Arginine Pathway in Sepsis

描述(由申请人提供)： 克里斯蒂娜·高博士是贝勒医学院(BCM)肺、重症监护和睡眠医学部的助理教授。她的短期目标是发展使用稳定同位素方法进行新陈代谢研究的知识和技能。她的长期目标是成为一名研究危重疾病和肺部疾病的营养和代谢方面的独立研究员。高博士参加了BCM临床科学家培训计划的MS Track，她可以使用德克萨斯医学中心的广泛资源，包括儿童营养研究中心和一个多医院系统。高博士将研究谷氨酰胺和精氨酸之间的代谢关系。这些氨基酸通过器官间途径联系在一起，包括谷氨酰胺在肠道内转化为瓜氨酸，然后肾脏摄取瓜氨酸并转化为精氨酸。她提出，在败血症患者中，(A)谷氨酰胺可获得性以及全身和内脏代谢的改变将导致瓜氨酸和精氨酸合成减少，(B)补充谷氨酰胺将导致瓜氨酸合成增加，从而导致精氨酸合成增加。稳定同位素示踪方法将被用来检验这些假说的具体方面。具体目标1将确定败血症患者和健康对照组谷氨酰胺转化为瓜氨酸的速率和内脏部分谷氨酰胺提取物的差异。假设是败血症患者从谷氨酰胺合成瓜氨酸减少，瓜氨酸的产生速度与内脏提取谷氨酰胺的速度直接相关。特定目标2将确定败血症患者和健康对照组从其前体瓜氨酸和谷氨酰胺合成从头精氨酸的速率。该假说认为，败血症患者谷氨酰胺供应减少导致从头合成精氨酸减少。具体目标3将确定肠内和肠外补充谷氨酰胺对败血症患者精氨酸和瓜氨酸合成的影响。假设脓毒症患者补充谷氨酰胺将导致瓜氨酸和从头精氨酸合成增加，而且与肠外补充相比，这种增加的幅度更大。 与公共健康相关：精氨酸和谷氨酰胺这两种化合物有助于我们的身体对抗严重的感染。这项研究将有助于更好地确定这两种化合物之间的关系，并将确定供应更多的一种(谷氨酰胺)是否会反过来导致另一种(精氨酸)的增加。更好地了解身体对这两种化合物的利用有助于改善严重感染患者的营养治疗。

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.