Investigating Syndecan-1 in Hepcidin Regulation and Iron Metabolism

总结 Syndecan-1在铁调素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有机体功能。有机铁含量受饮食控制 铁的吸收、红细胞中的铁分配、巨噬细胞的铁再循环和肝细胞中的铁储存。 激素铁调素是全身铁含量的主要调节剂，因为它负调节膜铁转运蛋白， 主要的细胞铁输出蛋白，介导铁从肠细胞、巨噬细胞和肝细胞流入 流通我们已经表明，硫酸乙酰肝素是铁调素调控的关键组成部分。乙酰肝素抑制 肝细胞瘤细胞和小鼠中硫酸盐生物合成减少基线、BMP 6刺激和IL 6刺激 hepcidin表达与贫血的病理生理学特征有关。我们现在已经 基于遗传学和免疫组织化学， 药理学失活人和小鼠肝癌细胞中的多配体蛋白聚糖-1表达。我们的研究结果 这意味着内源性肝多配体蛋白聚糖-1作为模板支持信号复合物调节 铁调素表达和铁代谢。我们建议将我们的研究扩展到人类肝细胞; 确定Sdc 1介导的铁调素调节的潜在机制 表达;并利用这些信息来开发治疗以以下特征为特征的疾病的策略： 铁超载为了实现这些目标，我们将（i）检查syndecan-1在驱动基础和铁- 人肝细胞中可诱导的铁调素表达;（ii）确定syndecan-1调节人肝细胞中铁调素表达的机制。 （iii）评估遗传和药理学多配体蛋白聚糖-1靶向 纠正铁负荷疾病模型中的铁稳态失调。本提案的总体目标是 评估syndecan-1结构与铁代谢的关系，长期目标是确定新的铁代谢途径。 潜在的目标，以减少铁负荷紊乱的风险，如炎症性贫血。

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.