Function of metal transporter ZIP14 as regulated by proinflammatory stimuli

促炎刺激调节金属转运蛋白 ZIP14 的功能

• 批准号: 8535747
• 负责人: ROBERT J COUSINS
• 金额: $ 27.67万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-23 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535747
• 关键词: Address; Anti-Inflammatory Agents; Biochemical; Breeding; CREB1 gene; Calcineurin; Calcium; Carrier Proteins; Cell Proliferation; Cells; Cytoplasm; Dietary Intervention; Dietary Zinc; Drug Design; Drug Targeting; Gastrointestinal tract structure; Gene Family; Genes; Genetic Transcription; Health; Health Promotion; Hepatic; Hepatocyte; Homeostasis; Hormones; Human; IL6 gene; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-12; Ion Transport; Ions; Iron; Knockout Mice; Liver; Liver Regeneration; Lysosomes; Mediating; Metals; Micronutrients; Mission; Modeling; Mus; Muscle; Nitric Oxide; Outcome; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Physiology; Protein Kinase; Protein phosphatase; Proto-Oncogene Protein c-met; Research; Research Project Grants; Role; Signal Pathway; Signal Transduction; Site; Small Intestines; Stimulus; Supplementation; T-Lymphocyte; Testing; Up-Regulation; Zinc; cytokine; embryonic stem cell; functional outcomes; in vivo; knockout gene; promoter; research study; therapeutic target; transcription factor; zinc-binding protein

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.

描述（由申请人提供）：锌是维持健康所需的必需微量营养素。潜在的机制尚不清楚，但越来越多的证据表明锌在控制信号通路中发挥作用，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，其细胞内离子浓度控制功能。细胞使用源自两个基因家族的 24 种不同的锌转运蛋白将锌离子引导至细胞内位点。一些锌转运蛋白基因对饮食中的锌供应做出反应并参与体内平衡，而其他一些基因则受细胞因子和激素的调节。我们已经鉴定出两个锌转运蛋白基因 Zip8 和 Zip14，它们对促炎细胞因子有反应。 ZIP8 介导的 Zn2+ 从活化 T 细胞溶酶体的转运将 CREB ​​维持在其磷酸化论坛中，从而增强 IFNy 转录。我们已经证明，在 IL6、IL12 和一氧化氮的刺激下，Zip14 在肝细胞中被诱导。 ZIP14 刺激 Zn2+ 转运并具有功能结果，例如与金属响应转录因子 MTF1 相互作用。该提案的重点是使用 Zip14 敲除小鼠探索 ZIP14 的生理作用。我们对该项目的假设是，Zip14 会受到促炎性疾病的上调，并转运锌以实现肝脏、胃肠道和肌肉的功能。我们将通过三个相互关联的具体目标来检验我们的假设： 1. 表征 Zip14-/- 小鼠的表型，包括 Zip14 缺失对体内和原代细胞中金属转运的影响。 2. 评估 ZIP14 在小鼠肝脏再生和炎症反应过程中的参与。 3.炎症期间肝脏、胃肠道和肌肉信号通路中Zip14缺失和表达的生理后果。这些实验的基本原理是 ZIP14 (SLC39A14) 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 ZIP14 活性的药物。