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: 10474422
• 负责人: Airie Kim
• 金额: $ 38.04万
• 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/10474422
• 关键词: Ablation; Alveolar; Anemia; Attenuated; Biological Process; Blood; Blood Circulation; Cell membrane; Cell physiology; Cells; Clinical; Clinical Management; Cytosol; Data; Diagnosis; Disease; Embryo; Embryonic Development; Epithelial; 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; Manganese; Mediating; Metals; Micronutrients; Mus; Mutation; Nutrient; Nutritional Immunity; Nutritional Requirements; Other Genetics; Outcome; Pathologic; Pathologic Processes; Pathology; Patients; Phenotype; Physiological; Physiological Processes; Placenta; Play; 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; base; 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; macrophage; 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是通过细胞膜和从亚细胞隔室中的二价金属的跨膜进口商进入胞质空间。尽管GWAS数据暗示了无数严重的病理学中功能性ZIP8突变，但在稳态或病理状况下研究其功能的机理研究很少。我们创建了两个新颖的Zip8敲除（KO）小鼠模型，以研究该转运蛋白，可诱导的全身KO和一个肺上皮特异性KO，我们的初步数据表明ZIP8在肺宿主免疫，脾脏recycling和胎盘营养的转运中的重要作用。具体目标1。将Zip8作为金属转运蛋白的功能在对肺部感染的免疫反应中。肺中的Zip8表达高于任何其他器官系统，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，从肺泡空间中进口铁，在炎症刺激和革兰氏阴性细菌感染中都上调，并且对于抗抗氧化剂锰超氧抗氧化物歧化酶的抗氧化剂米磷脂剂（lpsoys）的诱导非常重要。我们将使用放射性金属示踪剂来表征Zip8介导的Fe，Zn和MN的运输，并研究Zip8对革兰氏阴性细菌和真菌肺部感染结果的影响。具体目的2。定义Zip8在脾巨噬细胞红细胞吞噬作用和铁回收中的作用。我们的初步数据表明，脾ZIP8主要在巨噬细胞中表达，Zip8缺失诱导红浆巨噬细胞和血清铁限制内的脾铁固隔，而脾zip8表达受脾脏铁水平的调节。我们将确定脾巨噬细胞中Zip8的位置，活动和调节。使用铁超负荷，铁缺乏和溶血的小鼠模型，我们还将表征Zip8在基线稳态和压力期间铁回收中的功能。具体目标3。定义Zip8对胎盘中母性营养转运的贡献。胎盘是人类中第二高Zip8的组织类型，小鼠中的全局Zip8消融是胚胎致死的。我们的初步数据表明，胎盘zip8在合成型成素细胞中表达，表明Zip8在营养金属从母体循环到胚胎中的运输中的关键作用。我们将使用新型的滋养细胞特异性Zip8 KO小鼠来定义Zip8在Fe，Zn和MN胎盘运输中的作用，使用原代人滋养细胞进行验证性研究，并根据母体铁的状态调查ZIP8。我们的建议将回答有关金属介导的肺部免疫，脾铁回收和养分金属胎盘运输中这种关键金属转运蛋白的病理生理功能的基本问题。这些发现将为我们在诊断和管理与金属稳态中断相关的许多病理方面的临床方法提供信息。