The research described in this proposal aims to investigate the molecular mechanisms involved in the abnormal iron accumulation observed in the disease, hereditary hemochromatosis (HH).
In Specific Aim 1, the hypothesis that levels of SFT (Stimulator of Fe Transport) mRNA and protein are increased in the liver and duodenum of HFE-knockout mice will be tested. Because humans with HH lack functional HFE protein, the HFE-knockout mouse is the best available animal model for studying the human disease. Expression of SFT in various other tissues will also be measured to determine the pattern of expression of SFT.
In Specific Aim 2, HeLa cells that over-express HFE will be transfected with SFT and transferrin-mediated iron uptake will be measured. The goal is to determine if increased expression of SFT will increase transferrin-mediated iron uptake, which has been found to be decreased in these cells.
In Specific Aim 3, antisense strategies will be used to block the expression of SFT in HeLa cells, which do not express detectable levels of HFE.
Specific Aim 3 will determine if the blocking of SFT expression will decrease transferrin-mediated iron uptake in these cells. Together, these specific aims will be useful in elucidating the molecular mechanisms involved in the abnormal iron metabolism of HH.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK009998-01A1
Application #
6139940
Study Section
Biological Sciences 2 (BIOL)
Program Officer
Podskalny, Judith M,
Project Start
2000-10-01
Project End
Budget Start
2000-10-01
Budget End
2001-09-30
Support Year
1
Fiscal Year
2000
Total Cost
$37,516
Indirect Cost
Name
Harvard University
Department
Nutrition
Type
Schools of Public Health
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Brain, Joseph D; Heilig, Elizabeth; Donaghey, Thomas C et al. (2006) Effects of iron status on transpulmonary transport and tissue distribution of Mn and Fe. Am J Respir Cell Mol Biol 34:330-7
Knutson, Mitchell; Menzies, Sharon; Connor, James et al. (2004) Developmental, regional, and cellular expression of SFT/UbcH5A and DMT1 mRNA in brain. J Neurosci Res 76:633-41
Knutson, Mitchell D; Vafa, Mohammad R; Haile, David J et al. (2003) Iron loading and erythrophagocytosis increase ferroportin 1 (FPN1) expression in J774 macrophages. Blood 102:4191-7
Knutson, M D; Levy, J E; Andrews, N C et al. (2001) Expression of stimulator of Fe transport is not enhanced in Hfe knockout mice. J Nutr 131:1459-64