The objective of the studies described herein is directed at defining the biochemical basis for the impairment in protein synthesis that characterizes the metabolic response to sepsis. Sustained loss of skeletal muscle protein contributes to the morbidity and mortality associated with sepsis. By understanding the derangements in the process of protein synthesis it is hoped that new strategies could be developed to combat the severe muscle wasting associated with the septic episode. We have established that two regulatory steps in the process of mRNA translation initiation phase of protein synthesis in skeletal muscle become inhibited during sepsis. These two loci are the reactions catalyzed by elF2B and the assembly of an active elF4E.elF4G complex. We hypothesize that the normal pathways in muscle responsible for maintaining the functioning of these two steps in mRNA translation initiation are severely compromised during sepsis. Once we have clarified the altered regulation of these two steps in sepsis, we will investigate different approaches (e.g. anti-cytokine therapies; amino acids; IGF-I) to circumvent the derangements identified.
The Specific Aims for the forthcoming project period are: 1) To define the mechanism(s) by which sepsis increases the phosphorylation of the E-subunit of elF2BE in skeletal muscle by examining the regulation of glycogen synthase kinase 3; 2) To examine the role of phosphorylation of elF4G in the control of formation of elF4E.elF4G complex in gastrocnemius of septic rats; 3) To determine the role of rapamycin-Insensitive pathway in the control of formation of elF4E.elF4G complex during sepsis following provision of amino acids and to delineate the signal transduction pathways regulated by amino acids through cDNA Expression Array analysis; and 4) To examine the mechanism by which IGF-I, but not insulin, decreases phosphorylation of elF2BE and/or increases formation of the active elF4E.elF4G complex in the stimulation of protein synthesis during sepsis. To accomplish these aims we will use a carefully characterized rat model of chronic, intra-abdominal sepsis whereby we can dissociate the effects of sterile inflammation from those of sepsis. The proposed studies should lead to potential new therapies to limit the loss of skeletal muscle protein during sepsis.
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