Protein Synthesis in Inflammation and Sepsis and in Development of Alcoholic Cardiomyopathy

The laboaratory has two main focuses both related to the control of protein synthesis. The first are is the efects of systemic bacterial infection on loss of muscle mass. The ceond area involves the examination of the efects of acute and chronic alcohol ingstion on the development of myocardial dysfunction leading to alcoholic cardiomyopathy.
Chronic sepsis is the leading cause of mortality in surgical intensive care units and results in profound muscle wasting of skeletal muscle which limits recovery from the disease state. The overall goal of the research program is to provide fundamental information regarding the mechanisms by which sepsis alters specific events in the protein synthetic pathway in skeletal muscle. We have identified two sites in the pathway of mRNA translation initiation that are altered by the septic process; namely the reaction catalyzed by the eukaryotic initiation factor 2B (eIF2B) and the assembly of the active eIF4E·eIF4G complex. Elucidating the processes involved in the dysregulation of these two steps during sepsis will be the overall goal of our studies. Specifically, we wish to establish the ability of amino acids and IGF-I to overcome the sepsis-induced defects in protein synthesis as a potential therapeutic modality to limit the complications of sepsis.
Alcoholism remains the most common form of drug abuse in the United States. Heart disease, as well as cirrhosis, represents an important etiology of mortality in chronic alcoholics. Excessive ethanol consumption can result in a syndrome termed alcoholic heart muscle disease. The long-term goal of this project is to gain a better understanding of the mechanisms by which chronic alcohol consumption induces myofibrillar damage characteristic of alcoholic heart muscle disease. It is our hypothesis that chronic alcohol consumption induces specific defects in the regulation of protein synthesis in cardiac muscle, which are responsible for the development of an alcohol-induced loss of myocardial protein. Preliminary studies have demonstrated that alcohol feeding for 12 weeks reduces the global rate of protein synthesis by approximately 30% in cardiac muscle. Furthermore, the defect in protein synthesis is localized to an inhibition of translational efficiency, rather than by decreasing the abundance of ribosomes. The diminished translational efficiency results from a fall in both peptide-chain initiation and elongation. The proposed studies will investigate the mechanisms by which chronic alcohol intoxication limits myocardial protein synthesis by reducing translation efficiency.