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: 10337222
• 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/10337222
• 关键词: Anemia; Anemia due to Chronic Disorder; Antisense Oligonucleotides; Automobile Driving; BMP6 gene; Blood Circulation; Brucella abortus; CRISPR/Cas technology; Characteristics; Chronic Kidney Failure; 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; Hormones; Human; IL6 gene; Inflammation; Interleukin-6; Iron; Iron Overload; Knowledge; Ligands; Liver; Measures; Mediating; Modeling; Mus; Natural History; Pharmacology; Proteomics; Recycling; Regulation; Risk; Role; Signal Transduction; Signaling Protein; Structure; System; Testing; Tissues; Trace Elements; Transcriptional Regulation; absorption; base; bone morphogenic protein; clinically relevant; dietary; efficacy evaluation; hepatoma cell; hepcidin; improved; induced pluripotent stem cell; interest; iron absorption; iron metabolism; macrophage; metal transporting protein 1; mouse model; mutant; new therapeutic target; novel; 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.

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