ZIP8: A Metal Transporter with Pathophysiologic Roles in the Lung, Spleen, and Placenta

ZIP8：在肺、脾和胎盘中具有病理生理作用的金属转运蛋白

• 批准号: 10678928
• 负责人: Airie Kim
• 金额: $ 39万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678928
• 关键词: Ablation; Acceleration; Alveolar; Anemia; Attenuated; Biological Process; Blood; Cell membrane; Cell physiology; Cells; Circulation; Clinical; Clinical Management; Cytosol; Data; Diagnosis; Disease; Embryo; Embryo Transfer; Embryonic Development; Epithelium; Erythrocytes; Erythrophagocytosis; Erythropoiesis; Fetal Development; Future; Gram-Negative Bacterial Infections; Health; Hematological Disease; Hematopoietic; Hemoglobinopathies; Hemolysis; Hemorrhage; Homeostasis; Human; Immune response; Immunity; In Vitro; Infection; Inflammation; Inflammatory; Innate Immune Response; Iron; Iron Overload; Knock-out; Knockout Mice; Lipopolysaccharides; Location; Lung; Lung infections; Macrophage; Manganese; Mediating; Membrane; Metals; Micronutrients; Mus; Mutation; Nutrient; Nutritional Immunity; Nutritional Requirements; Other Genetics; Outcome; Pathologic; Pathologic Processes; Pathology; Patients; Phenotype; Physiological; Physiological Processes; Placenta; Pneumonia; Pregnancy; Proteins; Public Health; Pulmonary Inflammation; Radioactive; Radioactive metal; Recovery; Recycling; Regulation; Research; Research Personnel; Role; SOD2 gene; Serum; Spleen; Splenic Red Pulp; Stimulus; Stress; Syncytiotrophoblast; System; Tissues; Trace metal; Tracer; Zinc; Zinc deficiency; alveolar epithelium; antioxidant enzyme; body system; career; clinical development; defined contribution; differential expression; divalent metal; enzyme mechanism; fetal; genome wide association study; in vitro Model; iron deficiency; lung injury; mouse model; novel; novel therapeutics; oxidative damage; pathogenic microbe; tool; transcription factor; trophoblast

ZIP8 is a transmembrane importer of divalent metals into the cytosolic space through the cell membrane and from subcellular compartments. Although GWAS data implicate hypofunctional ZIP8 mutations in a myriad of serious pathologies, there is a paucity of mechanistic studies investigating its functions during homeostasis or pathologic conditions. We have created two novel ZIP8 knockout (KO) mouse models in order to study this transporter, an inducible whole-body KO and a lung epithelium-specific KO, and our preliminary data indicate significant roles of ZIP8 in lung host immunity, splenic iron recycling, and placental nutrient transport. Specific Aim 1. Define the functions of ZIP8 as a metal transporter in the immune response to lung infections. ZIP8 expression is higher in the lung than in any other organ system, but its biological function is unknown. Our preliminary data show that lung ZIP8 is located primarily in the alveolar epithelium, where it imports iron from the alveolar space, is upregulated with both inflammatory stimuli and gram-negative bacterial infection, and is important for induction of the antioxidant enzyme manganese superoxide dismutase by lipopolysaccharide (LPS). We will characterize ZIP8-mediated transport of Fe, Zn, and Mn during both homeostasis and LPS lung injury using radioactive metal tracers, and study the effects of ZIP8 on the outcomes of gram-negative bacterial and fungal lung infections. Specific Aim 2. Define the role of ZIP8 in splenic macrophage erythrophagocytosis and iron recycling. Our preliminary data show that spleen ZIP8 is primarily expressed in macrophages, ZIP8 deletion induces splenic iron sequestration within red pulp macrophages and serum iron restriction, and spleen ZIP8 expression is regulated by splenic iron levels. We will identify the location, activity, and regulation of ZIP8 within splenic macrophages. Using mouse models of altered iron handling with iron overload, iron deficiency, and hemolysis, we will also characterize the function of ZIP8 in iron recycling during both baseline homeostasis and stress. Specific Aim 3. Define the contribution of ZIP8 to maternal-fetal nutrient transport in the placenta. The placenta is the second highest ZIP8-expressing tissue type in humans, and global ZIP8 ablation in mice is embryonic lethal. Our preliminary data show that placental ZIP8 is expressed in syncytiotrophoblasts, indicating a key role of ZIP8 in the transport of nutrient metals from maternal circulation to the embryo. We will use a novel trophoblast specific ZIP8 KO mouse to define the role of ZIP8 in placental transport of Fe, Zn, and Mn, perform confirmatory studies using primary human trophoblasts, and investigate ZIP8 regulation by maternal iron status. Our proposal will answer fundamental questions about the pathophysiologic functions of this critical metal transporter in metal-mediated lung host immunity, splenic iron recycling, and placental transport of nutrient metals. The findings will inform our clinical approaches in diagnosing and managing the many pathologies associated with disrupted metal homeostasis.

ZIP8是通过细胞膜和亚细胞区室将二价金属导入细胞质空间的跨膜进口商。尽管GWAS数据表明ZIP8在许多严重的病理中都存在功能低下的突变，但在体内平衡或病理状态下调查其功能的机制研究却很缺乏。为了研究这种转运体，我们建立了两种新的ZIP8敲除（KO）小鼠模型，一种是可诱导的全身KO，一种是肺上皮特异性KO，我们的初步数据表明ZIP8在肺宿主免疫、脾铁循环和胎盘营养物质运输中起着重要作用。具体目标确定ZIP8作为金属转运体在肺部感染免疫应答中的功能。ZIP8在肺中的表达高于其他任何器官系统，但其生物学功能尚不清楚。我们的初步数据表明，肺ZIP8主要位于肺泡上皮，它从肺泡间隙进口铁，在炎症刺激和革兰氏阴性细菌感染时上调，并且在脂多糖（LPS）诱导抗氧化酶锰超氧化物歧化酶中起重要作用。我们将使用放射性金属示踪剂表征ZIP8介导的铁、锌和锰在体内平衡和LPS肺损伤过程中的转运，并研究ZIP8对革兰氏阴性细菌和真菌肺部感染结果的影响。具体目标2。确定ZIP8在脾巨噬细胞红细胞吞噬和铁循环中的作用。我们的初步数据表明，脾脏ZIP8主要在巨噬细胞中表达，ZIP8缺失导致红髓巨噬细胞内脾铁固存和血清铁限制，脾脏ZIP8的表达受脾铁水平的调控。我们将确定ZIP8在脾巨噬细胞中的位置、活性和调控。利用铁超载、铁缺乏和溶血改变的小鼠铁处理模型，我们还将描述ZIP8在基线稳态和应激期间铁循环中的功能。具体目标3。确定ZIP8对胎盘中母胎营养转运的贡献。胎盘是人类体内第二高表达ZIP8的组织类型，在小鼠中，ZIP8的整体消融是胚胎致命的。我们的初步数据表明，胎盘ZIP8在合胞滋养细胞中表达，表明ZIP8在营养金属从母体循环到胚胎的运输中起关键作用。我们将使用一种新型的滋养细胞特异性ZIP8 KO小鼠来确定ZIP8在Fe， Zn和Mn的胎盘运输中的作用，使用原代人滋养细胞进行验证性研究，并研究母体铁状态对ZIP8的调节。我们的建议将回答这个关键的金属转运体在金属介导的肺宿主免疫、脾铁循环和营养金属的胎盘运输中的病理生理功能的基本问题。这些发现将为我们诊断和管理与金属稳态紊乱相关的许多病理的临床方法提供信息。