Syndecan-1 structure-function analysis in relation to iron metabolism

项目总结/摘要 铁是一种重要的微量矿物质，参与重要的细胞和系统功能。人类和其他 脊椎动物需要足够的铁供应来执行基本的代谢功能和氧运输 同时保持体内平衡的铁水平以防止铁中毒。有机铁含量由以下因素控制： 膳食吸收、红细胞中的铁分配、巨噬细胞的铁再循环以及 肝细胞精确的机制已经发展到保存铁储存和调节铁输送到组织。一 该系统的关键成员是hepcidin，一种肝源性肽激素。铁调素是一种主要的调节剂， 通过其负调节膜铁转运蛋白（ferroportin）的能力实现系统性铁稳态，膜铁转运蛋白是唯一已知的哺乳动物膜铁转运蛋白。 铁输出者铁调素合成通过升高的血清铁水平生理活化， 病理上是由炎症和感染引起的。铁调素的表达被增加的红细胞生成抑制 需求硫酸乙酰肝素（HS）是细胞糖萼的一个重要聚糖部分，最近被确定为 hepcidin调节的关键组分。原代人肝癌细胞中HS生物合成的抑制 肝细胞，小鼠降低基线和刺激铁调素表达，并恶化 炎症性贫血的病理生理学特征。初步研究发现Syndecan-1 （SDC-1），肝脏中的主要硫酸乙酰肝素蛋白聚糖（HSPG），作为一种新的细胞表面受体， 参与hepcidin调节。SDC-1的遗传和药理学失活证明， hepcidin表达在人肝癌模型中是SDC-1依赖性的。然而，其精确的作用方式 仍有待阐明。拟议的研究将（i）验证SDC-1作为调节基础胰岛素分泌的关键HSPG， 和可诱导的铁调素表达，鉴定铁稳态调节的一个新的分支，（ii）阐明 SDC-1在体外调节铁调素的机制，这可以为控制铁调素提供新的见解。 铁稳态和（iii）使用体内肝特异性SDC-1失活来研究SDC-1的影响 消耗和结构改变对全身铁稳态的影响。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 新的潜在目标，以减少铁负荷障碍的风险，如血色素沉着症和贫血， 炎症

Project Summary/Abstract Iron is an essential trace mineral involved in vital cellular and systemic functions. Humans and other vertebrates require a sufficient iron supply to carry out essential metabolic functions and oxygen transport while maintaining homeostatic iron levels to prevent iron toxicity. Organismal iron content is controlled by dietary absorption, iron partitioning in erythrocytes, iron recycling by macrophages, and iron storage in hepatocytes. Precise machinery has evolved to conserve iron stores and regulate iron delivery to tissues. A critical member of this system is hepcidin, a liver-derived peptide hormone. Hepcidin is a master regulator of systemic iron homeostasis through its ability to negatively regulate ferroportin, the sole known mammalian iron-exporter in the cell. Hepcidin synthesis is activated physiologically by elevated serum iron level and pathologically by inflammation and infection. Hepcidin expression is repressed by increased erythropoietic demand. Heparan sulfate (HS), a prominent glycan part of the cell glycocalyx, was recently established as a critical component of hepcidin regulation. Inhibition of HS biosynthesis in hepatoma cells, primary human hepatocytes, and mice reduced baseline and stimulated hepcidin expression and worsened the pathophysiology characteristic of anemia of inflammation. Preliminary studies have identified Syndecan-1 (SDC-1), the primary heparan sulfate proteoglycan (HSPG) in the liver, as a novel cell surface receptor involved in hepcidin regulation. Genetic and pharmacological inactivation of SDC-1 demonstrated that hepcidin expression is SDC-1-dependent in human hepatoma models. However, its precise mode of action remains to be elucidated. The proposed study will (i) validate SDC-1 as the key HSPG that regulates basal and inducible hepcidin expression, identifying a novel arm of iron homeostasis modulation, (ii) elucidate the mechanism by which SDC-1 regulates hepcidin in vitro which can provide novel insights into the control of iron homeostasis and (iii) use in vivo liver-specific SDC-1 inactivation to study the impact of SDC-1 depletion and structural alteration on systemic iron homeostasis. 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 hemochromatosis and anemia of inflammation.