Ferroportin 1 in vertebrate iron utilization

铁转运蛋白 1 在脊椎动物铁利用中的作用

• 批准号: 6492324
• 负责人: LEONARD Ira ZON
• 金额: $ 24.14万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-01-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6492324
• 关键词: developmental genetics; erythropoiesis; gastrointestinal nutrient absorption; gene expression; gene targeting; genetic screening; ion transport; iron metabolism; laboratory mouse; membrane transport proteins; nutrition related tag; protein structure function; transcription factor; transfection; zebrafish

Efficient uptake and utilization of iron is essential to normal hematopoiesis. In mammals, dietary iron absorption is carried out by specialized enterocytes in the proximal small intestine. Iron is taken up through the apical transmembrane iron transport, DMT1, Homozygous mutant mice carrying a mutation in DMT1 are severely iron deficient and poorly viable. Until recently, it was not known host iron exists the basolateral surface of the enterocyte to reach the circulation. We recently identified a transmembrane protein, ferroportin1, which as an iron exporter. The ferroportin1 gene is defective in the zebrafish mutant weissherbst. Weissherbst embryos die from severe iron deficiency anemia, resulting from defective iron transport between the yolk sac and the developing embryo. The mammalian ortholog of ferroportin1 is expressed in the basolateral membrane of intestinal enterocytes, and at other sites requiring active iron expert. We hypothesize that ferroportin1 is the basolateral iron transporter in enterocytes and an iron exporter in other cell types In this grant we propose to study the conservation of vertebrate ferroportin1 function and the role of ferroportin1 in vivo. Gene targeting will be used to generate mice lacking ferroportin1 in selected tissues and these animals will be analyzed for defects in iron absorption and homeostasis. Ferroportin1 expression and activity will be analyzed in a panel of mouse mutants with defects in iron metabolism, and in a murine model of human hemochromatosis. Zebrafish studies will investigate the relationship between erythropoiesis and ferroportin1 by studying mRNA expression in known hematopoietic mutants. A mutagenesis screen will also be done to find zebrafish mutants with defects in ferroportin1 mRNA expression. Finally, we plan to do also be done to find zebrafish mutants with defects in ferroportin1 mRNA expression. Finally, we plan to do a suppressor-enhancer screen for ferroportin1 to define factors that genetically coordinate iron metabolism with ferroportin1 in the developing zebrafish embryo. Our findings will improve our understanding of vertebrate iron biology and may be relevant to human patients with iron deficiency and iron overload disorders.

铁的有效吸收和利用对于正常造血至关重要。在哺乳动物中，膳食铁的吸收是由近端小肠的专门肠细胞进行的。铁是通过顶端跨膜铁转运 DMT1 吸收的，携带 DMT1 突变的纯合突变小鼠严重缺铁且生存能力差。直到最近，人们还不知道宿主铁存在于肠上皮细胞的基底外侧表面以到达循环。我们最近发现了一种跨膜蛋白，ferroportin1，它是铁的输出蛋白。斑马鱼突变体 weissherbst 中的膜铁转运蛋白 1 基因有缺陷。 Weissherbst 胚胎死于严重缺铁性贫血，这是由于卵黄囊和发育中胚胎之间的铁运输缺陷造成的。 Ferroportin1 的哺乳动物直系同源物在肠肠上皮细胞的基底外侧膜以及需要活性铁专家的其他位点表达。我们假设ferroportin1是肠细胞中的基底外侧铁转运蛋白，也是其他细胞类型中的铁输出蛋白。在这项资助中，我们建议研究脊椎动物ferroportin1功能的保守性以及ferroportin1在体内的作用。基因打靶将用于产生在选定组织中缺乏铁转运蛋白1的小鼠，并将分析这些动物的铁吸收和体内平衡缺陷。将在一组具有铁代谢缺陷的小鼠突变体和人类血色素沉着病的小鼠模型中分析 Ferroportin1 的表达和活性。斑马鱼研究将通过研究已知造血突变体中的 mRNA 表达来研究红细胞生成和膜铁转运蛋白 1 之间的关系。还将进行诱变筛选，以寻找具有膜铁转运蛋白 1 mRNA 表达缺陷的斑马鱼突变体。最后，我们还计划寻找具有膜铁转运蛋白 1 mRNA 表达缺陷的斑马鱼突变体。最后，我们计划对ferroportin1进行抑制-增强子筛选，以确定在发育中的斑马鱼胚胎中与ferroportin1在基因上协调铁代谢的因素。我们的研究结果将提高我们对脊椎动物铁生物学的理解，并可能与患有缺铁和铁过载疾病的人类患者相关。