Iron is the most abundant transition metal in the human body and an essential nutrient. Toxicity results when cellular free iron catalyzes the formation of destructive free radicals. Aging, atherosclerosis, arthritis, are some of the increasing list of human conditions in which iron catalyzed generation of free radicals is suspected to contribute to tissue injury. To minimize toxicity, the iron content of the body tightly regulates uptake of iron through the duodenal epithelium. The central hypothesis of this application is that the control of duodenal iron export is primarily transcriptional and that this transcriptional control is independent of duodenal epithelial cell iron content. This hypothesis has been formulated on the basis of strong preliminary evidence from my laboratory that a) the regulation of MTP1 by iron is the opposite of the regulation observed with other 5' IRE containing genes, such as ferritin, b) the duodenal epithelial expression of MTP1 is independent of iron content of the epithelial cell itself. I plan to test the hypothesis and accomplish the objectives of this grant proposal by completing the following specific aims: 1. Measure MTP1 mRNA and protein levels and transcription rates in duodenal sections of normal, mk, sla and hpx mice with varying amounts of total body iron. 2. Determine the structure of the 5' UTR of the MTP1 mRNA induced with iron deprivation in duodenal epithelial cells. 3. Characterize the role of the 5' UTR IRE of MTP1 in the iron dependent regulation of the gene. This approach is expected to yield the following results: a) Identification of the mode of regulation of MTP1 by iron in the duodenum. b) Characterization of the role of the differing 5' UTRs of MTP1 in the iron dependent regulation of the gene. Identification of the mechanisms of the regulation by iron of components responsible for iron absorption will result in a better understanding of overall iron metabolism and will lead to better therapeutic strategies for limiting cellular damage secondary to iron derived free radicals.
| Chung, Jayong; Haile, David J; Wessling-Resnick, Marianne (2004) Copper-induced ferroportin-1 expression in J774 macrophages is associated with increased iron efflux. Proc Natl Acad Sci U S A 101:2700-5 |
| 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 |
