The long-term goal of this Program Project and the Hershey Iron Group is to define the molecular and cellular interactions controlling iron regulation and function. The understanding of 1) the mechanisms of intestinal iron egress; 2) intracellular iron compartmentalization; 3) iron-mediated gene regulation; 4) intracellular iron-regulatory protein flux nd 5) the intricate cellular and molecular feedback mechanisms which maintain iron balance are all areas toward which the Program Project team is expected to contribute. Specifically, the individual aims are 1) to determine the structure, processing and expression of the hemochromatosis disease gene within the in vitro and in vivo systems and particularly in the context of iron challenge; 2) to study the regulation of the iron- regulatory proteins (IRPs) by focusing on post-transcriptional modifications and mechanisms of intracellular translocation following cytokine and iron stimulation; and 3) to understand the cytokine-induced molecular mechanisms effecting iron mobilization and flux within a well- defined, iron-loaded primary hepatocyte culture system. This Program Project draws together three research laboratories within the Pennsylvania State University College of Medicine with i) proven track records in the molecular biological and genetic studies of iron metabolism, ii) complementing research interests; iii) established collaborations and well-recognized synergy. The specific proposals, entitled """"""""Biological function of the hemochromatosis disease gene"""""""" (Project 1-Chorney); """"""""Post-transcriptional regulation of iron regulatory proteins"""""""" (Project 2-Conner) and """"""""Molecular and cellular control transcriptional regulation of iron regulatory proteins"""""""" (Project 2-Conner) and """"""""Molecular and cellular control mechanisms in iron-loaded hepatocytes"""""""" (Project 3-Isom) engender a natural connectedness which will facilitate the intellectual movement between systems. The Program Project will receive foundation support from a Core encompassing """"""""Metal Analysis and Molecular Genetics"""""""" contained within the broader Division of Research Resources (Billingsley) which will further ensure cogent interactions through the sharing of reagents and technologies. It is anticipated that the group will contribute much to the understanding of the physiological processes underlying iron flux and utilization in both health and disease states such as iron overload and anemia, Alzheimer's disease and malignancy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK053430-04
Application #
6489703
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (O4))
Program Officer
Badman, David G
Project Start
1999-02-01
Project End
2003-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
4
Fiscal Year
2002
Total Cost
$546,266
Indirect Cost
Name
Pennsylvania State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Patton, Stephanie M; Pinero, Domingo J; Surguladze, Nodar et al. (2005) Subcellular localization of iron regulatory proteins to Golgi and ER membranes. J Cell Sci 118:4365-73
Henderson, Rebecca J; Patton, Stephanie M; Connor, James R (2005) Development of a fluorescent reporter to assess iron regulatory protein activity in living cells. Biochim Biophys Acta 1743:162-8
Grundy, Martin A; Gorman, Nadia; Sinclair, Peter R et al. (2004) High-throughput non-heme iron assay for animal tissues. J Biochem Biophys Methods 59:195-200
Bilello, John P; Cable, Edward E; Isom, Harriet C (2003) Expression of E-cadherin and other paracellular junction genes is decreased in iron-loaded hepatocytes. Am J Pathol 162:1323-38
Bilello, J P; Cable, E E; Myers, R L et al. (2003) Role of paracellular junction complexes in baculovirus-mediated gene transfer to nondividing rat hepatocytes. Gene Ther 10:733-49
Iocca, Heather A; Isom, Harriet C (2003) Tumor necrosis factor-alpha acts as a complete mitogen for primary rat hepatocytes. Am J Pathol 163:465-76
Stoehr, Stephanie A; Isom, Harriet C (2003) Gap junction-mediated intercellular communication in a long-term primary mouse hepatocyte culture system. Hepatology 38:1125-35
Chorney, Michael J; Yoshida, Yukinori; Meyer, Paul N et al. (2003) The enigmatic role of the hemochromatosis protein (HFE) in iron absorption. Trends Mol Med 9:118-25
Cable, Edward E; Kuhn, Benjamin R; Isom, Harriet C (2002) Effects of modulators of protein phosphorylation on heme metabolism in human hepatic cells: induction of delta-aminolevulinic synthase mRNA and protein by okadaic acid. DNA Cell Biol 21:323-32
Malecki, Elise A; Cable, Edward E; Isom, Harriet C et al. (2002) The lipophilic iron compound TMH-ferrocene [(3,5,5-trimethylhexanoyl)ferrocene] increases iron concentrations, neuronal L-ferritin, and heme oxygenase in brains of BALB/c mice. Biol Trace Elem Res 86:73-84

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