This application addresses the broad Challenge Area 15, Translational Sciences, and specific challenge topic 15-DK-103: Translate discovery of new molecules and pathways in pathogenesis of NIDDK diseases into potential therapies, diagnostics, or research tools. The biochemistry of iron transport is not thoroughly understood. Although iron deficiency is the most prevalent nutritional problem in the U.S., 1 in 20 Caucasians carry genetic variants of HFE alleles that promote susceptibility to iron overload. Thus, there is a need to develop new therapeutic strategies for diseases of both iron deficiency and overload. Through high-throughput fluorescence-based screening, our lab recently discovered that ferristatin (NSC306711) inhibits both of the major iron transport processes that maintain homeostasis: transferrin- mediated iron uptake and non-transferrin-bound iron uptake by Divalent Metal Transporter 1 (DMT1). Chlorazol black (NSC8679) is structurally similar and has comparable effects on transport. This project will further investigate the impact of these two small molecules and related compounds in vivo, on a) pharmacokinetics of intestinal iron uptake to the vasculature;b) iron uptake into erythroid cells and hepatic non-transferrin bound iron uptake;and c) iron homeostasis and reversal of overload. These efforts will further our goals to elucidate the biochemical processes regulating iron homeostasis, and to provide a foundation for the development of targeted small-molecule therapies for states of anemia and hemochromatosis.
Iron deficiency remains the most prevalent nutritional problem in our country, yet recent identification of the gene responsible for hereditary hemochromatosis indicates that 1 in 20 Caucasians carry the defective allele and thus 1 in 400 may be susceptible to iron overload. Increased knowledge about the transport factors and how they protect against iron deficiency and overload is essential to more broadly address these significant health problems.
| Kim, Jonghan; Jia, Xuming; Buckett, Peter D et al. (2013) Iron loading impairs lipoprotein lipase activity and promotes hypertriglyceridemia. FASEB J 27:1657-63 |
| Jia, Xuming; Kim, Jonghan; Veuthey, Tania et al. (2013) Glucose metabolism in the Belgrade rat, a model of iron-loading anemia. Am J Physiol Gastrointest Liver Physiol 304:G1095-102 |
| Byrne, Shaina L; Krishnamurthy, Divya; Wessling-Resnick, Marianne (2013) Pharmacology of iron transport. Annu Rev Pharmacol Toxicol 53:17-36 |
| Wessling-Resnick, Marianne (2010) Iron homeostasis and the inflammatory response. Annu Rev Nutr 30:105-22 |
