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 研究 Syndecan-1 在 Hepcidin 调节和铁代谢中的作用。铁是人体必需的微量矿物质， 参与许多重要的细胞和有机体功能。有机铁含量由饮食控制 吸收、铁在红细胞中的分配、巨噬细胞的铁回收以及肝细胞中的铁储存。 激素铁调素是全身铁含量的主要调节剂，因为它对铁转运蛋白（铁转运蛋白）进行负调节。 原代细胞铁输出蛋白介导铁从肠细胞、巨噬细胞和肝细胞流入 循环。我们已经证明硫酸乙酰肝素是铁调素调节的关键成分。乙酰肝素的抑制作用 肝癌细胞和小鼠中的硫酸盐生物合成降低基线、BMP6 刺激和 IL6 刺激 铁调素表达并恶化炎症性贫血的病理生理学特征。我们现在有 基于遗传和遗传因素，确定 syndecan-1 是调节肝脏 hepcidin 表达的主要 HSPG 人和小鼠肝癌细胞中 syndecan-1 表达的药理失活。我们的发现 暗示内源性肝 syndecan-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；到 确定 Sdc1 介导的铁调素调节所需的潜在机制 表达;并利用这些信息来制定治疗以下疾病的策略 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 调节机制 hepcidin 表达和 (iii) 评估遗传和药理学 syndecan-1 靶向的功效 纠正铁负荷疾病模型中的铁稳态失调。该提案的总体目标是 评估 syndecan-1 结构与铁代谢的关系，长期目标是定义新的 降低铁负荷紊乱风险的潜在目标，例如炎症性贫血。