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 #
5R37ES002497-29
Application #
7236043
Study Section
Nutrition Study Section (NTN)
Program Officer
Lawler, Cindy P
Project Start
1987-06-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
29
Fiscal Year
2007
Total Cost
$442,299
Indirect Cost
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
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