Our objective is to understand the relationship between selenium (Se) deficiency in humans and experimental animals to glutathione peroxidase (GSHPx) as it effects the ability of cells to metabolize peroxides and respond to an oxidative stress.
The aim i s to expand studies designed to examine the molecular, cellular and functional consequences of Se deficiency. One objective is related to the observation that in Se deficient states of humans and rats there is a parallel decrease in GSHPx protein and activity.
The first aim i s to determine whether this decrease in protein content is due to decreased synthesis or increased degradation or combinations of the two. This will be accomplished by examining the effects of Se deficiency on the transcription of the m-RNA for GSHPx and protein synthesis both in vitro and in vivo. Proteolysis of an abnormal protein will also be searched for. Another objective of this proposal is related to another recent observation that the Se dependent plasma GSHPx activity is immunologically and biochemically distinct from the cellular enzyme.
The second aim i s to purify and characterize the plasma enzyme, determine its source and the relationship of its protein to activity in Se deficient states. Polyclonal antibodies made against the purified plasma enzyme will be used to determine the cellular origin of the enzyme and whether the protein is present in Se deficiency. In order to to determine the physiologic role of GSHPx a third aim of this proposal is to determine the functional consequences of Se deficiency as it relates to the metabolism of H2O2 and the sensitivity of Se deficient cells to an oxidative stress. The ability of blood cells and cell lines to respond to a source of peroxides will be determined as will the effects of other manipulators of the glutathione cycle on Se deficient cell function. Since the clinical effects of Se deficiency are only now being describe and may relate in part to sensitivity to oxidative stress, it is important to understand what happens to cellular metabolism and function when this occurs.
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