The nutritional effects of selenium depend on selenoproteins. Selenoprotein P (Se-P) is an extracellular selenoprotein that has been postulated to transport the element from the liver to other tissues. In past grant periods we have shown that Se-P accounts for most of the selenium flux through rat plasma and that the brain up regulates its acquisition of selenium from Se-P in selenium deficiency. In the present grant period, we have identified a heparin binding site and 4 glycosylation sites on rat Se-P. We have characterized 4 isoforms of Se-P. Three of them terminate at UGAs in the mRNA and the 4 tb is full length. This indicates that some UGA codons have alternative functions of termination and designation of selenocysteine insertion. We have also produced mice with deletion of the Se-P gene (Sepp). Sepp -/ mice have male infertility. When fed a low selenium diet, they develop axonal degeneration in the brain stem with severe neurological dysfunction. Testis and brain have low selenium concentrations in Sepp -/- mice, indicating that both organs depend on Se-P for some of their selenium. We propose to characterize selenium homeostasis, using Sepp -/- mice and mice with deletion of the other plasma selenoprotein, GPX-3, with special emphasis on the brain. This will pinpoint regions of the brain dependent on Se-P (and possibly GPX-3) for selenium. Using immunoaffinity methods, we will seek to identify a receptor for Se-P in the brain and to characterize it. Then the receptor will be mapped using immunocytochemistry. We will use morphological methods to determine brain regions in which cells degenerate in Sepp -/- mice fed a low selenium diet. Results of these studies will be interpreted to characterize the brain injury with the objective of selecting human neurological disorders to study for genetic abnormalities of Se-P and its receptor.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Method to Extend Research in Time (MERIT) Award (R37)
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Nutrition Study Section (NTN)
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Lawler, Cindy P
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Vanderbilt University Medical Center
Internal Medicine/Medicine
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Wu, Sen; Mariotti, Marco; Santesmasses, Didac et al. (2016) Human selenoprotein P and S variant mRNAs with different numbers of SECIS elements and inferences from mutant mice of the roles of multiple SECIS elements. Open Biol 6:
Mao, Jinyuan; Pop, Victor J; Bath, Sarah C et al. (2016) Effect of low-dose selenium on thyroid autoimmunity and thyroid function in UK pregnant women with mild-to-moderate iodine deficiency. Eur J Nutr 55:55-61
Barrett, Caitlyn W; Reddy, Vishruth K; Short, Sarah P et al. (2015) Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage. J Clin Invest 125:2646-60
Rayman, Margaret P; Bath, Sarah C; Westaway, Jacob et al. (2015) Selenium status in U.K. pregnant women and its relationship with hypertensive conditions of pregnancy. Br J Nutr 113:249-58
Burk, Raymond F; Hill, Kristina E (2015) Regulation of Selenium Metabolism and Transport. Annu Rev Nutr 35:109-34
Burk, Raymond F; Hill, Kristina E; Motley, Amy K et al. (2015) Selenium deficiency occurs in some patients with moderate-to-severe cirrhosis and can be corrected by administration of selenate but not selenomethionine: a randomized controlled trial. Am J Clin Nutr 102:1126-33
Burk, Raymond F; Hill, Kristina E; Motley, Amy K et al. (2014) Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration. FASEB J 28:3579-88
Kurokawa, Suguru; Eriksson, Sofi; Rose, Kristie L et al. (2014) Sepp1(UF) forms are N-terminal selenoprotein P truncations that have peroxidase activity when coupled with thioredoxin reductase-1. Free Radic Biol Med 69:67-76
Rayman, Margaret P; Searle, Elizabeth; Kelly, Lynne et al. (2014) Effect of selenium on markers of risk of pre-eclampsia in UK pregnant women: a randomised, controlled pilot trial. Br J Nutr 112:99-111
Hill, Kristina E; Motley, Amy K; Winfrey, Virginia P et al. (2014) Selenoprotein P is the major selenium transport protein in mouse milk. PLoS One 9:e103486

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