Abstract

The overall long-term goal of this project continues to be directed at understanding the involvement of zinc binding proteins and those proteins that interact with zinc for the absorption, metabolism, and biological function of dietary zinc. The project aims are interrelated.
Aim 1. Functional Significance of Metallothionein (MT) Expression in Human and Murine Cells and Tissues. Using quantitative PCR (Q-PCR), assays for hMT and specific zinc transporter genes of both the SLC30 and SLC39 families will be used in controlled zinc depletion and zinc supplementation studies with human subjects to evaluate the zinc responsiveness of these genes in monocytes and T cells. The influence of murine MT, as regulated by dietary zinc, will be evaluated as a factor in nitrosative stress. These experiments will use MT null and inducible nitric oxide (NO) synthase null genotypes and focus on isolated liver parenchymal cells in culture and targets of NO, viz., intestinal cells.
Aim II. Characterization of Zinc Responsive Genes. These studies will focus on THP1 cells as a model for human mononuclear cells using chelator-induced zinc depletion and supplementation. Comparisons will be made between zinc-responsive genes ? LPS activation. Similar studies will compare zinc-responsive genes of thymocytes ? LPS from zinc-deficient and zinc-supplemented mice. Analysis will be by microarrays, with confirmation by proteomics. Responsiveness of the MTF1 and MTF2 transcription factors to dietary zinc will be compared.
Aim III. Murine Zinc Transporters and Their Response to Dietary Zinc Intake and Physiologic Mediators. The IL-6 responsive transporter Zip14 will be further characterized with transfected cells and for a role in inflammatory hypozincemia. Expression of zinc transporter genes of the reticuloendothelial system during the acute phase response will be evaluated. The zinc processing steps the pancreatic acinar cells and Paneth cells use for endogenous zinc release will receive close attention. Extensive use will be made of transporter localization using immunohistochemistry and immunocytochemistry and zinc fluorophores as visualized by fluorescence microscopy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031127-28
Application #
7642543
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
1982-07-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2011-06-30
Support Year
28
Fiscal Year
2009
Total Cost
$308,805
Indirect Cost

  Institution

Name
University of Florida
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611

  Publications

Aydemir, Tolunay Beker; Chang, Shou-Mei; Guthrie, Gregory J et al. (2012) Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia). PLoS One 7:e48679
Aydemir, Tolunay Beker; Sitren, Harry S; Cousins, Robert J (2012) The zinc transporter Zip14 influences c-Met phosphorylation and hepatocyte proliferation during liver regeneration in mice. Gastroenterology 142:1536-46.e5
Ryu, Moon-Suhn; Guthrie, Gregory J; Maki, Alyssa B et al. (2012) Proteomic analysis shows the upregulation of erythrocyte dematin in zinc-restricted human subjects. Am J Clin Nutr 95:1096-102
Pinilla-Tenas, Jorge J; Sparkman, Brian K; Shawki, Ali et al. (2011) Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. Am J Physiol Cell Physiol 301:C862-71
Ryu, Moon-Suhn; Langkamp-Henken, Bobbi; Chang, Shou-Mei et al. (2011) Genomic analysis, cytokine expression, and microRNA profiling reveal biomarkers of human dietary zinc depletion and homeostasis. Proc Natl Acad Sci U S A 108:20970-5
Lichten, Louis A; Ryu, Moon-Suhn; Guo, Liang et al. (2011) MTF-1-mediated repression of the zinc transporter Zip10 is alleviated by zinc restriction. PLoS One 6:e21526
Guo, Liang; Lichten, Louis A; Ryu, Moon-Suhn et al. (2010) STAT5-glucocorticoid receptor interaction and MTF-1 regulate the expression of ZnT2 (Slc30a2) in pancreatic acinar cells. Proc Natl Acad Sci U S A 107:2818-23
Cousins, Robert J; Aydemir, Tolunay B; Lichten, Louis A (2010) Plenary Lecture 2: Transcription factors, regulatory elements and nutrient-gene communication. Proc Nutr Soc 69:91-4
Cousins, Robert J (2010) Gastrointestinal factors influencing zinc absorption and homeostasis. Int J Vitam Nutr Res 80:243-8
Liuzzi, Juan P; Guo, Liang; Chang, Shou-Mei et al. (2009) Krüppel-like factor 4 regulates adaptive expression of the zinc transporter Zip4 in mouse small intestine. Am J Physiol Gastrointest Liver Physiol 296:G517-23

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