The plan of research is based on the evidence that severe burn injury
initiates a unique series of changes in the homeostasis of nitrogen
metabolism and that of the major energy-yielding substrates, glucose
and lipids. Severe injury also profoundly alters the integration
of inter-organ cooperatively in overall nitrogen and energy economy
of the host. The net effect of these changes is an overall nitrogen
catabolic state, which seriously compromises wound healing and recovery
and is refractory to treat with current therapies. These changes
lead to a functional redistribution of nitrogen (amino acids and
proteins) and substrate metabolism among the wounded tissues and
major body organs. This redistribution of substrate results in a
quantitative reordering of the usual pathways of carbon and nitrogen
flow within and among regions of the body with resulting depletion
of required substrates and cofactors in important organs.
The Project and Cores
Our research program is organized into four projects that focus
on the interrelated aspects of specific amino acid, glucose, and
fatty acid metabolism. For over thirty years, we have evaluated
the roles of amino acids in the post-injury state. The selected
glutamine, arginine, and sulfur-containing amino acids (methionine
and cysteine) have been proven to be critical in the regulation
of nitrogen and energy metabolism. The Center also includes other
core components in support of the four research projects: PET and
μPET Core, Mass and NMR Spectroscopy Core, Human Studies Core
and Administration Core.
Project 1: Amino Acid Interrelations and
Metabolism
Project 1 focuses on the whole-body level of amino acid-nitrogen-energy
metabolism and its response to severe trauma in patients. Within
Project 1, several studies are conducted to improve our understanding
of the roles of three major organs (muscle, liver, and intestines)
in overall nitrogen-amino acid homeostasis.
Project 2: Tissue-Specific Metabolic Response
to Injury
Project 2 focuses on the role of skeletal muscle in the nitrogen-energy
metabolism after severe injury in patients. Methionine incorporation
and release from protein is used as a measure of protein synthesis
and degradation in skeletal muscle. Because insulin and its receptor
are key contributors to maintenance of the anabolic state, diminished
effectiveness of post-receptor events is likely to be a pathway,
which plays a major role in the catabolic post-injury state. Therefore,
we have chosen, in Projects 3 and 4, to delineate specific molecular
abnormalities in post-receptor events after injury.
Project 3: Molecular Mechanisms of Burn-Induced
Insulin Resistance
Project 3 evaluates molecular abnormalities in proximal post-receptor
events at the level of insulin receptor substrate (IRS-1), which
we have shown to be abnormal in burn injury.
Project 4: Muscle Wasting in Burns: the
Pivotal Role of Akt/PKB
Project 4 determines molecular abnormalities in more distal post-receptor
events at the level of Akt/PKB, which we believe is another important
level of control in the post-receptor signaling pathway. The Akt/PKB
complex is important in mitochondrial integrity, regulation of apoptosis,
and generation of the metabolic actions of insulin.
[top]
|
