The transport of heme by the plasma protein, hemopexin, into tissues such as the liver is a specific, receptor-mediated process. As a result of this hepatic reclamation of heme, biologically useful iron is conserved, the accumulation of toxic heme is prevented and the growth of invading microorganisms is inhibited. The ultimate goals of our research are 1) to delineate the biochemical mechanism of heme transport by hemopexin - from the initial binding of heme in the circulation to the final intracellular localization of heme and heme-iron - and 2) to identify and characterize the intracellular consequences of hemopexin-mediated heme transport. With regards to this second objective, recent studies in this laboratory indicate that hemopexin-mediated heme transport modulates gene expression, including the induction of heme oxygenase and metallothionein synthesis and down-regulation of the synthesis of the transferrin receptor. The major goal of this proposal then is to characterize the mechanisms by which hemopexin-mediated heme transport into liver cells stimulates the expression of heme oxygenase and metallothionein. In particular, we will: 1) identify and determine the mode of action of specific DNA sequences that are involved in the heme-hemopexin-dependent stimulation of heme oxygenase and metallothionein gene transcription; 2) characterize these DNA sequence elements with respect their specific protein binding capacity; 3) isolate and characterize the DNA-binding proteins involved this regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK043135-02
Application #
3244457
Study Section
Physical Biochemistry Study Section (PB)
Project Start
1991-09-15
Project End
1995-08-31
Budget Start
1992-09-01
Budget End
1993-08-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Ochsner Clinic Foundation
Department
Type
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70121
Zhang, Xuchen; Shan, Peiying; Alam, Jawed et al. (2005) Carbon monoxide differentially modulates STAT1 and STAT3 and inhibits apoptosis via a phosphatidylinositol 3-kinase/Akt and p38 kinase-dependent STAT3 pathway during anoxia-reoxygenation injury. J Biol Chem 280:8714-21
Gonzalez-Michaca, Luis; Farrugia, Gianrico; Croatt, Anthony J et al. (2004) Heme: a determinant of life and death in renal tubular epithelial cells. Am J Physiol Renal Physiol 286:F370-7
Zhang, Xuchen; Shan, Peiying; Alam, Jawed et al. (2003) Carbon monoxide modulates Fas/Fas ligand, caspases, and Bcl-2 family proteins via the p38alpha mitogen-activated protein kinase pathway during ischemia-reperfusion lung injury. J Biol Chem 278:22061-70
Alam, Jawed; Killeen, Erin; Gong, Pengfei et al. (2003) Heme activates the heme oxygenase-1 gene in renal epithelial cells by stabilizing Nrf2. Am J Physiol Renal Physiol 284:F743-52
Zhang, Xuchen; Shan, Peiying; Otterbein, Leo E et al. (2003) Carbon monoxide inhibition of apoptosis during ischemia-reperfusion lung injury is dependent on the p38 mitogen-activated protein kinase pathway and involves caspase 3. J Biol Chem 278:1248-58
Kanakiriya, Sharan K R; Croatt, Anthony J; Haggard, Jill J et al. (2003) Heme: a novel inducer of MCP-1 through HO-dependent and HO-independent mechanisms. Am J Physiol Renal Physiol 284:F546-54
Lu, Huasheng; Hunt, Diana Margaret; Ganti, Ramapriya et al. (2002) Metallothionein protects retinal pigment epithelial cells against apoptosis and oxidative stress. Exp Eye Res 74:83-92
Zhang, Xuchen; Bedard, Eric L; Potter, Richard et al. (2002) Mitogen-activated protein kinases regulate HO-1 gene transcription after ischemia-reperfusion lung injury. Am J Physiol Lung Cell Mol Physiol 283:L815-29
Gong, Pengfei; Stewart, Daniel; Hu, Bin et al. (2002) Multiple basic-leucine zipper proteins regulate induction of the mouse heme oxygenase-1 gene by arsenite. Arch Biochem Biophys 405:265-74
Gong, Pengfei; Stewart, Daniel; Hu, Bin et al. (2002) Activation of the mouse heme oxygenase-1 gene by 15-deoxy-Delta(12,14)-prostaglandin J(2) is mediated by the stress response elements and transcription factor Nrf2. Antioxid Redox Signal 4:249-57

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