PROJECTS

Project 1:
Amino Acid Interrelations and Metabolism

Project 2:
Tissue-Specific Metabolic Response to Injury

Project 3:
Molecular Mechanisms of Burn-Induced Insulin Resistance

Project 4:
Muscle Wasting in Burns: the Role of Akt/PKB


TECHNOLOGY CORES

PET and µPET Facility

Spectroscopy Facilities


SUPPORT CORES

Human Studies Research

Administration







































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Brief Narrative

Alterations in the regulation of energy and amino acid metabolism, especially involving a disturbance in the inter-organ integration of amino acid metabolism following burn injury, are of etiological importance in morbidity and mortality. The signals and factors responsible for the changes in amino acid substrate and inter-organ metabolism appear to be unique to the injured host and triggered by changes in the inflammatory system. Amino acids and especially those that have been categorized as the "conditionally indispensable amino acids" play important roles in both protein and non-protein pathways of biosynthesis and function, including the TCA cycle. At a mechanistic level, this is achieved via a high degree of metabolic compartmentation, which may be compromised as a consequence of the inflammatory response and altered hormonal / protein mediator profile. This compromise leads to a single or multiple conditionally indispensable amino acid deficiency.

Hypothesis Guiding the Research

A protein catabolic state contributes to increased morbidity and mortality in severely stressed patients and is causally related to an alteration in the regulation and flow of amino acids along the protein and non-protein pathways, including those of significance in energy metabolism. These alterations necessitate identification and quantification to improve the design of mixtures of amino acids or their precursors for optimal nutritional support of burn patients.

The project focuses on the "conditionally indispensable" amino acids glutamine, arginine, and the sulfur amino acids, especially cysteine, to further dissect out the changes that occur in their metabolism and utilization, and the functional consequences as a basis for determining whether their altered availability is of etiological significance in the clinical response to severe illness.

Specific Aims

Specific Aim 1 evaluates the status of glutamine metabolism, in relation to its role in both glucose and energy substrate metabolism, and the maintenance of the protein and nitrogen economy. Additional studies in model systems include the use of a hyperglutaminemic clamp and mass spectrometry to assess the major fate of glutamine in the pathways of carbon and nitrogen metabolism following burn injury.

Specific Aim 2 examines the status and nutritional factors, especially the sulfur amino acids that affect GSH metabolism in burn patients and model systems. We seek to determine the roles of the conditionally indispensable amino acid precursors of GSH synthesis (glutamine, glycine and cysteine) in the regulation of GSH metabolism after burn injury.

Specific Aim 3 further explores the status of arginine metabolism and the regulatory factors of nitric oxide (NO) synthesis after burn injury, in relation to organ function (effect of arginine supply and the metabolic modulation of NO synthesis in different organs, especially the lungs, liver, and the kidney). The study includes an initial determination of the potential significance of both asymmetric dimethyl-arginine and homocysteine in the interplay between arginine and NO metabolism.

Specific Aim 4 further develops and applies a new mass isotopomer method in three stepwise studies. (A) Initial determination of albumin synthesis rate in model systems to subsequently adapt this method to (B) assess the synthesis rate of acute phase proteins, including CRP, and fibronectin, and Apo B100 in model systems, and eventually to (C) assess the synthesis of other anabolic mediator career proteins, at different stages of recovery from burn injury in patients.

Innovation

The investigations in this project over thirty-plus years have contributed seminal knowledge about amino acid and intermediary metabolism in injury and health. These studies have yielded important and clinically relevant information regarding the metabolism and possible requirements of these amino acids during periods of burn injury and in healthy human subjects. A better understanding of amino acid (nitrogen) and glucose/energy metabolism and how it is affected by the stress of burn injury should lead to optimal nutritional and pharmacological therapy for patients.

For more information about this project, please contact Dr. Joanne Kelleher or Dr. Yong-Ming Yu.

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