Investigating Syndecan-1 in Hepcidin Regulation and Iron Metabolism

研究 Syndecan-1 在 Hepcidin 调节和铁代谢中的作用

• 批准号: 10527368
• 负责人: Philip Gordts
• 金额: $ 60.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10527368
• 关键词: Anemia; Anemia due to Chronic Disorder; Antisense Oligonucleotides; Automobile Driving; BMP6 gene; Bone Morphogenetic Proteins; Brucella abortus; CRISPR/Cas technology; Characteristics; Chronic Kidney Failure; Circulation; Complex; Disease; Disease model; Enterocytes; Erythrocytes; Erythropoiesis; Exhibits; Functional disorder; Genetic; Goals; Hematological Disease; Heparan Sulfate Biosynthesis; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Hepatic; Hepatocyte; Homeostasis; Hormone secretion; Hormones; Human; IL6 gene; Inflammation; Interleukin-6; Iron; Iron Overload; Knowledge; Ligands; Liver; Macrophage; Measures; Mediating; Modeling; Mus; Natural History; Proteomics; Recycling; Regulation; Risk Reduction; Role; Signal Transduction; Signaling Protein; Structure; System; Testing; Tissues; Trace Elements; Transcriptional Regulation; absorption; clinically relevant; dietary; efficacy evaluation; hepatoma cell; hepcidin; improved; induced pluripotent stem cell; interest; iron absorption; iron metabolism; metal transporting protein 1; mouse model; mutant; new therapeutic target; novel; pharmacologic; pre-clinical; prevent; receptor; reconstitution; syndecan

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.

概括 在肝素调节和铁代谢中研究Syndecan-1。铁是必不可少的痕量矿物， 参与许多重要的细胞和生物功能。有机铁含量由饮食控制 吸收，红细胞中的铁分配，巨噬细胞的铁回收以及肝细胞中的铁储存。 激素，肝素是全身铁含量的主要调节剂，因为它会对铁杆菌进行负调节， 一级细胞铁出口商从肠细胞，巨噬细胞和肝细胞中介导铁流 循环。我们已经表明，硫酸乙酰肝素是肝素调节的关键组成部分。抑制乙酰肝素 肝癌细胞和小鼠中硫酸盐的生物合成可降低基线，BMP6刺激，IL6刺激 肝素表达，并使炎症性贫血的病理生理特征恶化。我们现在有 根据遗传和 在人和小鼠肝癌细胞中syndecan-1表达的药理灭活。我们的发现 暗示内源性肝syndecan-1充当支持调节信号复合物的模板 肝素表达和铁代谢。我们建议将研究扩展到人类肝细胞。到 确定SDC1介导的肝素调节的基础机制 表达;并利用这些信息来制定策略来治疗以 铁超载。为了实现这些目标，我们将（i）研究Syndecan-1在驱动基础和铁中的作用 在人肝细胞中诱导型肝素表达； （ii）确定syndecan-1调控的机理 肝素表达和（iii）评估遗传学和药理学Syndecan-1靶向的疗效 在铁载疾病模型中正确的铁dyshomeostasis。该提议的总体目标是 评估Syndecan-1结构与铁代谢的关系，其远程目标是定义新的 降低富含铁疾病的风险的潜在靶标，例如炎症贫血。