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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要铁是一种重要的微量矿物质，参与重要的细胞和系统功能。人类和其他脊椎动物需要足够的铁供应来执行基本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。有机铁含量由以下因素控制饮食吸收、红细胞中的铁分配、巨噬细胞的铁回收以及体内铁的储存肝细胞。精密机械已经发展到可以保存铁储备并调节铁向组织的输送。一个该系统的关键成员是铁调素，一种肝源性肽激素。 Hepcidin 是主要调节因子通过负向调节铁转运蛋白（唯一已知的哺乳动物）的能力来实现全身铁稳态细胞内的铁输出者。血清铁水平升高会在生理上激活铁调素合成，病理上由炎症和感染引起。铁调素的表达受到红细胞生成增加的抑制要求。硫酸乙酰肝素 (HS) 是细胞糖萼的重要聚糖部分，最近被确定为铁调素调节的关键组成部分。抑制人原代肝癌细胞中 HS 生物合成肝细胞和小鼠降低基线并刺激铁调素表达并使病情恶化炎症性贫血的病理生理学特征。初步研究已确定 Syndecan-1 (SDC-1)，肝脏中的主要硫酸乙酰肝素蛋白多糖 (HSPG)，作为一种新型细胞表面受体参与铁调素调节。 SDC-1 的遗传和药理学失活表明在人类肝癌模型中，hepcidin 的表达依赖于 SDC-1。然而，其精确的作用方式仍有待阐明。拟议的研究将 (i) 验证 SDC-1 作为调节基础的关键 HSPG 和诱导性铁调素表达，确定铁稳态调节的新臂，（ii）阐明 SDC-1在体外调节铁调素的机制，可以为控制铁调素提供新的见解铁稳态和 (iii) 使用体内肝脏特异性 SDC-1 失活来研究 SDC-1 的影响全身铁稳态的消耗和结构改变。该提案的总体目标是评估 Syndecan-1 结构与铁代谢的关系，长期目标是定义降低铁负荷疾病风险的新潜在目标，例如血色素沉着症和贫血炎。