Zinc is an essential micronutrient that is required to maintain health. The underlying mechanisms are unknown, but evidence is emerging that zinc has roles in control of signaling pathways, e.g. protein kinases, protein phosphatases and transcription factor phosphorylation. The role is similar to that of calcium where the intracellular ion concentration controls functions. Cells use 24 different zinc transporter proteins derived from two gene families to direct zinc ions to intracellular sites. Some zinc transporter genes respond to the dietary zinc supply and participate in homeostasis, whereas a few others are regulated by cytokines and hormones. We have identified two zinc transporter genes Zip8 and Zip14, which respond to proinflammatory cytokines. ZIP8 mediated transport of Zn2+ from lysosomes of activated T cells maintains CREB in its phosphorylated forum enabling enhanced IFNy transcription. We have demonstrated that Zip14 is induced in hepatocytes upon stimulation by IL6, IL12 and nitric oxide. ZIP14 stimulates Zn2+ transport and has functional outcomes such as interaction with the metal responsive transcription factor, MTF1. The focus of this proposal is to explore the physiologic role of ZIP14 using Zip14 knockout mice. Our hypothesis for this project is that Zip14 is up-regulated by pro-inflammatory conditions and transports zinc for functions in liver, the gastrointestinal tract, and muscle. We will test our hypothesis through three interconnected specific aims: 1. Characterize the phenotype of the Zip14-/- mouse including the effects of Zip14 deletion on metal transport in vivo and in primary cells. 2. Evaluate the involvement of ZIP14 in murine liver regeneration and during inflammatory responses. 3. Physiologic consequences of Zip14 Deletion and Expression in signaling pathways in liver, gastrointestinal tract and muscle during inflammation. The rationale for these experiments is that the ZIP14 (SLC39A14) transporter is responsive to proinflammatory stimuli and hence is dysregulated in many pathophysiologic conditions producing altered zinc signaling. These may benefit from zinc supplementation or drugs designed to influence ZIP14 activity.