Investigating Syndecan-1 in Hepcidin Regulation and Iron Metabolism

摘要 Syndecan-1在海普西丁调节和铁代谢中的研究铁是一种必需的微量矿物质， 参与许多重要的细胞和组织功能。人体铁含量受饮食控制 铁在红细胞中的吸收、分配、巨噬细胞中的铁循环和肝细胞中的铁储存。 荷尔蒙海普西丁是全身铁含量的主要调节者，因为它负向调节铁蛋白，即 初级细胞铁输出体介导肠细胞、巨噬细胞和肝细胞的铁流 发行量。我们已经证明，硫酸乙酰肝素是海普西丁调节的关键成分。肝素的抑制作用 肝癌细胞和小鼠体内硫酸盐的生物合成减少了基线、Bmp6刺激和IL6刺激 并加重炎症性贫血的病理生理特征。我们现在有了 根据基因和基因分析确定Syndecan-1是主要的HSPG，它调节肝脏海普西丁的表达 药物灭活人和小鼠肝癌细胞中Syndecan-1的表达。我们的发现 提示内源性肝Syndecan-1作为模板支持信号复合体调节 海普西丁的表达与铁代谢。我们建议将我们的研究扩展到人类肝细胞； 确定Sdc1介导的海普西丁调节的潜在机制 表达；并利用这些信息来开发治疗以以下特征为特征的障碍的策略 铁超载。为了实现这些目标，我们将(I)研究Syndecan-1在驱动基础和铁- 在人肝细胞中可诱导表达；(Ii)确定Syndecan-1调节的机制。 海普西丁的表达和(Iii)评价基因和药理学靶向的syndecan-1的疗效 纠正铁负荷性疾病模型中的铁代谢紊乱。这项提议的首要目标是 评估Syndecan-1结构与铁代谢的关系，长期目标是定义新的 潜在的目标是降低铁负荷紊乱的风险，如炎症贫血。

SUMMARY Investigating Syndecan-1 in Hepcidin Regulation and Iron Metabolism. Iron is an essential trace mineral, involved in many vital cellular and organismal functions. Organismal iron content is controlled by dietary absorption, iron partitioning in erythrocytes, iron recycling by macrophages and iron storage in hepatocytes. The hormone, hepcidin is a master regulator of systemic iron content as it negatively regulates ferroportin, the primary cellular iron exporter mediating iron flow from enterocytes, macrophages and hepatocytes into the circulation. We have shown that heparan sulfate is key component of hepcidin regulation. Inhibition of heparan sulfate biosynthesis in hepatoma cells and in mice reduces baseline, BMP6-stimulated, and IL6-stimulated hepcidin expression and worsens the pathophysiology characteristic of anemia of inflammation. We have now identified syndecan-1 as the primary HSPG regulating liver hepcidin expression based on genetic and pharmacological inactivation of syndecan-1 expression in human and mouse hepatoma cells. Our findings imply that endogenous hepatic syndecan-1 serves as a template to support signaling complexes regulating hepcidin expression and iron metabolism. We propose to extend our studies to human hepatocytes; to determine the mechanism underlying the requirement for Sdc1-mediated regulation of hepcidin expression; and to exploit this information to develop strategies to treat disorders characterized by iron overloading. To achieve these goals, we will (i) Examine the role of syndecan-1 in driving basal and iron- inducible hepcidin expression in human hepatocytes; (ii) Determine the mechanism of syndecan-1 regulation of hepcidin expression and (iii) Evaluate the efficacy of genetic and pharmacological syndecan-1 targeting to correct iron dyshomeostasis in iron-loading disease models. The overarching goal of this proposal is to evaluate the relationship of syndecan-1 structure to iron metabolism, with the long-range goal of defining new potential targets to reduce the risk of iron-loading disorders, such as anemia of inflammation.