Function of metal transporter ZIP14 as regulated by proinflammatory stimuli

描述（由申请人提供）：锌是维持健康所需的必需微量营养素。其潜在机制尚不清楚，但有证据表明锌在控制信号通路中起作用，例如蛋白激酶、蛋白磷酸酶和转录因子磷酸化。其作用类似于钙，其中细胞内离子浓度控制功能。细胞使用来自两个基因家族的24种不同的锌转运蛋白将锌离子引导到细胞内位点。一些锌转运蛋白基因响应于膳食锌供应并参与体内平衡，而另一些则受细胞因子和激素的调节。我们已经确定了两个锌转运蛋白基因Zip 8和Zip 14，响应于促炎细胞因子。ZIP 8介导的Zn 2+从活化的T细胞的溶酶体的转运将CREB维持在其磷酸化的论坛中，使得能够增强IFN γ转录。我们已经证明，Zip 14在肝细胞中被IL 6、IL 12和一氧化氮刺激后诱导。ZIP 14刺激Zn 2+转运并具有功能性结果，例如与金属响应转录因子MTF 1相互作用。本提案的重点是使用Zip 14敲除小鼠探索ZIP 14的生理作用。我们对该项目的假设是，Zip 14通过促炎条件上调，并在肝脏，胃肠道和肌肉中转运锌。我们将通过三个相互关联的具体目标来测试我们的假设：1。表征Zip 14-/-小鼠的表型，包括Zip 14缺失对体内和原代细胞中金属转运的影响。2.评估ZIP 14在小鼠肝再生和炎症反应中的参与。3.炎症期间肝脏、胃肠道和肌肉中Zip 14缺失和表达信号通路的生理后果。这些实验的基本原理是ZIP 14（SLC 39 A14）转运蛋白对促炎刺激有反应，因此在许多病理生理条件下失调，产生改变的锌信号传导。这些可能受益于锌补充剂或旨在影响ZIP 14活性的药物。

DESCRIPTION (provided by applicant): 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.