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

Syndecan-1 与铁代谢相关的结构功能分析

• 批准号: 10678445
• 负责人: Stephanie Leal
• 金额: $ 4.01万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678445
• 关键词: Address; Affect; Agreement; Anemia; Anemia due to Chronic Disorder; Automobile Driving; BMP6 gene; CRISPR/Cas technology; Cell Line; Cell Surface Receptors; Cell model; Cells; Characteristics; Co-Immunoprecipitations; Complex; Cre lox recombination system; Data; Diet; Disease; Doctor of Philosophy; Erythrocytes; Evaluation; Functional disorder; Genes; Genetic; Glycocalyx; Goals; HFE2 gene; Hematological Disease; Hemochromatosis; Hep3B; HepG2; Heparan Sulfate Biosynthesis; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Hepatic; Hepatocyte; Homeostasis; Human; In Vitro; Infection; Inflammation; Inflammatory; Interleukin 6 Receptor; Iron; Iron Overload; Knock-out; Knockout Mice; Ligands; Liver; Macrophage; Mediating; Metabolic; Modeling; Mus; Pathologic; Pathway interactions; Pharmacologic Substance; Physiological; Polysaccharides; Primary carcinoma of the liver cells; Production; Proteoglycan; Receptor Signaling; Recycling; Regulation; Repression; Risk Reduction; Role; Sample Size; Serum Iron Level; Signal Pathway; Signal Transduction; Structure; System; TFRC gene; Testing; Therapeutic; Time; Tissues; Toxic effect; Trace Elements; Training; Vertebrates; absorption; arm; bone morphogenetic protein receptors; crosslink; dietary; differential expression; experimental study; fibroglycan; hepatoma cell; hepcidin; in vivo; induced pluripotent stem cell; insight; iron metabolism; member; metal transporting protein 1; mouse model; mutant; novel; oxygen transport; peptide hormone; pharmacologic; polyclonal antibody; prevent; public repository; receptor; syndecan; transcriptome sequencing

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.

项目摘要/摘要 铁是参与重要细胞和全身功能的必不可少的痕量矿物。人类和其他 脊椎动物需要足够的铁供应才能执行必需的代谢功能和氧运输 同时保持稳态铁水平以防止铁毒性。有机铁含量由 饮食吸收，红细胞中的铁分配，巨噬细胞的铁回收以及铁在 肝细胞。精确的机械已经演变为保存铁储存并调节铁向组织的递送。一个 该系统的关键成员是肝脏衍生的肽激素Hepcidin。肝素是 系统性铁稳态通过其负调节铁托蛋白的能力（唯一已知的哺乳动物） 细胞中的铁爆炸蛋白。肝素合成通过血清铁水平升高和 在病理上通过炎症和感染。肝素表达因促红细胞生成而抑制 要求。硫酸乙酰肝素（HS）是细胞糖脂的突出的聚糖部分，最近被确定为 肝素调节的关键成分。抑制肝癌细胞中HS生物合成的抑制作用，原代人 肝细胞，小鼠降低了基线并刺激肝素表达，并使 炎症贫血的病理生理特征。初步研究已经确定了Syndecan-1 （SDC-1），肝脏中硫酸盐的主要硫酸盐蛋白聚糖（HSPG），作为一种新型细胞表面受体 参与肝素调节。 SDC-1的遗传和药理学失活表明 肝素表达在人肝癌模型中依赖于SDC-1。但是，其精确的行动方式 尚待阐明。拟议的研究将（i）验证SDC-1为调节基础的关键HSPG 和诱导性肝素表达，识别铁稳态调节的新手臂，（ii）阐明 SDC-1在体外调节肝素的机制，可以为控制提供新颖的见解 铁稳态和（iii）在体内肝特异性SDC-1失活中使用SDC-1的影响 全身铁稳态的耗竭和结构改变。该提议的总体目标是 评估Syndecan-1结构与铁代谢的关系，其远程目标是定义 降低铁负荷疾病风险的新潜在靶标，例如血色素症和贫血 炎。