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.
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