The objective is to continue our studies already begun fiv years ago to understand the way in which the body regulates protein and amino acid metabolism in vivo. We will continue to examine the interaction of various hormones in modulating the metabolism of the branched chain amino acids (BCAA) and their corresponding keto acids (BCKA). Over the past few years, our laboratory has been extensively involved in assessing these regulatory effects on the liver and forearm tissues in man, and the dog. We are presently planning to continue these studies in both man and the dog, and to examine the tissue sensitivities to these amino and keto acids during periods of fasting. We will also examine the modulatory role of two specific hormones, insulin and cortisol on these tissues. To adequately assess the direct interactions in vivo, it is necessary to measure 1) the total body flux of these amino and keto acids 2) and to examine the relative contributions of various organs to these fluxes. These are easily accomplished in the conscious dog model with catheters surgically implanted in an artery, and in the portal, hepatic, renal, and splenic veins; and when needed, in the sagital and coronary sinuses. Since these amino and ketoacids are presumed to primarily metabolized in skeletal muscle, we will examine the metabolism of these substances across the human forearm, and estimate the contribution of human skeletal muscle to their metabolism under vraious fasting, and hormonal preturbations. Utilizing these techniques we will (a) investigate the interorgan flow of these amino and keto acids in vivo. (b) Examine, whether these substrates can regulate their own metabolism. (c) Examine the sensitivities and specificities of the various tissues in the body to the metabolism of the BCAA and BCKA and, (d) Examine how the changes in these parameters with fasting. (d) Finally, we will examine how insulin glucocorticoids modulate their metabolism. These studies will provide insight into the mechanism of enhanced amino acid fluxes and protein breakdown during situations of excessive stress, or during periods of malnutrition. The ultimate hope is to be able to translate this information into improved health care for patients who are subjected to periods of excessive stress, such as trauma, injury, sepsis, diabetes mellitus, etc.
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