The overall long-term objective of our studies is to elucidate the molecular mechanisms involved in zinc homeostasis in mammals. Herein, we propose to study the rare, autosomal recessive trait, acrodermatitis enteropathic (AE). AE results for the inability to absorb significant dietary zinc, and a candidate gene mutated in human patients with AE was just identified. This gene encodes a member of the ZIP gene superfamily of metal transporters and was named hZIP4. We will test the hypothesis that this putative zinc transporter plays a central physiological role in zinc homeostasis using the mouse model. No mouse models for AE exist and essentially nothing is known about the regulation and functions of ZIP4. In preliminary studies, we have cloned the mouse ZIP4 gene and cDNA, determined that it is highly expressed in the intestinal tract, and demonstrated that mZIP4 mRNA is dramatically up-regulated during periods of dietary zinc deficiency. Therefore, the specific aims of this proposal are to: 1) Delineate the metal transport properties of native and AE mutants of mZIP4; 2) elucidate the mechanisms of metallo-regulation of mZIP4 expression; and 3) determine the affects of targeted mutation of the mZIP4 gene on zinc homeostasis in the mouse. This project represents a collaborative effort between the laboratories of Drs. Andrews, Eide, and Peterson. The P.I., Dr. Andrews is an expert in mammalian embryonic development and zinc deficiency, and in metalloregulation of gene expression. The Co-I., Dr. Eide is an expert and leader in the field of ZIP transporter function and regulation, and Co-I., Dr. Peterson is an expert in globin locus regulation and mouse knockout strategies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Nutrition Study Section (NTN)
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May, Michael K
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University of Kansas
Schools of Medicine
Kansas City
United States
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Geiser, Jim; De Lisle, Robert C; Finkelstein, David et al. (2013) Clioquinol synergistically augments rescue by zinc supplementation in a mouse model of acrodermatitis enteropathica. PLoS One 8:e72543
Geiser, Jim; De Lisle, Robert C; Andrews, Glen K (2013) The zinc transporter Zip5 (Slc39a5) regulates intestinal zinc excretion and protects the pancreas against zinc toxicity. PLoS One 8:e82149
Geiser, Jim; Venken, Koen J T; De Lisle, Robert C et al. (2012) A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity. PLoS Genet 8:e1002766
Weaver, Benjamin P; Andrews, Glen K (2012) Regulation of zinc-responsive Slc39a5 (Zip5) translation is mediated by conserved elements in the 3'-untranslated region. Biometals 25:319-35
Weaver, Benjamin P; Zhang, Yuxia; Hiscox, Stephen et al. (2010) Zip4 (Slc39a4) expression is activated in hepatocellular carcinomas and functions to repress apoptosis, enhance cell cycle and increase migration. PLoS One 5:
Kambe, Taiho; Andrews, Glen K (2009) Novel proteolytic processing of the ectodomain of the zinc transporter ZIP4 (SLC39A4) during zinc deficiency is inhibited by acrodermatitis enteropathica mutations. Mol Cell Biol 29:129-39
Belloni-Olivi, Luisa; Marshall, Cathleen; Laal, Bachchu et al. (2009) Localization of zip1 and zip4 mRNA in the adult rat brain. J Neurosci Res 87:3221-30
Kelleher, Shannon L; Lopez, Veronica; Lönnerdal, Bo et al. (2009) Zip3 (Slc39a3) functions in zinc reuptake from the alveolar lumen in lactating mammary gland. Am J Physiol Regul Integr Comp Physiol 297:R194-201
Andrews, Glen K (2008) Regulation and function of Zip4, the acrodermatitis enteropathica gene. Biochem Soc Trans 36:1242-6
Kambe, Taiho; Weaver, Benjamin P; Andrews, Glen K (2008) The genetics of essential metal homeostasis during development. Genesis 46:214-28

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