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

项目摘要/摘要 铁是一种必需的微量矿物质，与重要的细胞和系统功能有关。人类和其他 脊椎动物需要足够的铁供应来执行必要的代谢功能和氧气运输 同时保持体内平衡的铁水平，以防止铁中毒。有机铁含量受以下因素控制 膳食吸收，红细胞中铁的分配，巨噬细胞对铁的循环，以及体内铁的储存 肝细胞。精密机械已经发展起来，可以保存铁的储存，并调节铁向组织的输送。一个 这个系统的关键成员是海普西丁，一种来自肝脏的多肽激素。海普西丁是一种主要的调节剂 全身性铁稳态通过负向调节唯一已知的哺乳动物铁蛋白的能力 牢房里的铁输出物。海普西丁的合成在生理上是由升高的血清铁水平和 在病理学上由炎症和感染引起的。促红细胞生成素的增加抑制了海普西丁的表达 需求。硫酸乙酰肝素(HS)是细胞中的一种重要的糖基化部分，最近被确定为一种 海普西丁调节的关键成分。原代人肝癌细胞抑制HS生物合成的研究 肝细胞和小鼠降低基线和刺激海普西丁的表达，并恶化 炎症性贫血的病理生理特点。初步研究发现Syndecan-1 肝脏中主要的硫酸乙酰肝素蛋白多糖(SDC-1)作为一种新的细胞表面受体 参与了海普西丁的调节。SDC-1的遗传和药理失活表明 在人肝癌模型中，海普西丁的表达依赖于SDC-1。然而，它的确切行动模式 仍有待阐明。拟议的研究将(I)验证SDC-1作为调节基础 和可诱导的海普西丁表达，鉴定了一种新的铁稳态调节臂，(Ii)阐明了 SDC-1在体外调节海普西丁的机制，为控制肝细胞癌提供了新的视角 利用体内肝脏特异性SDC-1失活研究SDC-1对铁稳态的影响 全身性铁稳态的耗竭和结构改变。这项提议的首要目标是 评估Syndecan-1结构与铁代谢的关系，长期目标是确定 新的潜在目标，以减少铁负荷紊乱的风险，如血色素沉着症和贫血 发炎。

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.