The overall objective of these investigations is to understand the relationship between selenium (Se) status and glutathione peroxidase (GPx) in order to determine the role of Se in nutrition and the role of GPx as an antioxidant. During the past five years, we have identified, purified, and partially characterized a unique selenoglycoprotein present in plasma and other extracellular fluids that has GPx activity (e-GPx). The goals for this renewal application are 1) to determine the mechanisms(s) of post-transcriptional control of the expression of this protein relative to the cellular GPx by Se, 2) to determine its cell(s) and tissue(s) of origin and secretion in man and animals and 3) to examine the effect of renal disease on plasma GPx activity. We plan to examine the effects of doses and forms of Se on m-RNA, protein synthesis and enzymatic activity of both forms of GPx and to determine the relative contributions of translational control of protein synthesis, and protein stability to GPx activity changes. Since e-GPx is made and secreted by hepatocellular carcinoma, colon cancer, kidney cancer and both lung cell lines and a primary culture of lung cells, in addition to human placenta, and is present in plasma, lung lavage, kidney perfusates, and breast milk, we plan to examine its sites of synthesis and secretion using specific antibodies, cDNA probes and in situ hybridization. We also plan to perfuse rat kidneys to measures synthesis and secretion of e-GPx. Based on our preliminary data that renal disease and nephrectomy affect plasma GPx activity, we plan to perform longitudinal studies on the effect of renal disease and status on plasma GPx activity. The proposed investigations will enhance our understanding of cellular and molecular events associated with Se deficiency.
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