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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37ES002497-35
Application #
8476217
Study Section
Nutrition Study Section (NTN)
Program Officer
Lawler, Cindy P
Project Start
1987-06-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
35
Fiscal Year
2013
Total Cost
$485,410
Indirect Cost
$174,250
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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
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
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
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
Epplein, Meira; Burk, Raymond F; Cai, Qiuyin et al. (2014) A prospective study of plasma Selenoprotein P and lung cancer risk among low-income adults. Cancer Epidemiol Biomarkers Prev 23:1238-44
Burk, Raymond F; Olson, Gary E; Hill, Kristina E et al. (2013) Maternal-fetal transfer of selenium in the mouse. FASEB J 27:3249-56
Zhou, Xiaodong; Smith, Anne M; Failla, Mark L et al. (2012) Estrogen status alters tissue distribution and metabolism of selenium in female rats. J Nutr Biochem 23:532-8
Caito, Samuel W; Milatovic, Dejan; Hill, Kristina E et al. (2011) Progression of neurodegeneration and morphologic changes in the brains of juvenile mice with selenoprotein P deleted. Brain Res 1398:1-12
Masiulis, Irene; Quill, Timothy A; Burk, Raymond F et al. (2009) Differential functions of the Apoer2 intracellular domain in selenium uptake and cell signaling. Biol Chem 390:67-73
Hill, Kristina E; Motley, Amy K; May, James M et al. (2009) Combined selenium and vitamin C deficiency causes cell death in guinea pig skeletal muscle. Nutr Res 29:213-9

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