Using a small molecule iron transporter to understand and treat FPN1 deficiencies in mice

使用小分子铁转运蛋白来了解和治疗小鼠 FPN1 缺陷

• 批准号: 10181021
• 负责人: Martin D Burke
• 金额: $ 67.57万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-06 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10181021
• 关键词: Achievement; Acute; Address; Affect; Anemia; Anemia due to Chronic Disorder; Animal Model; Animals; Autoimmune Diseases; Biological Assay; Biological Markers; Bionics; Blood; Blood Transfusion; Cardiotoxicity; Carrier Proteins; Celiac Disease; Cells; Cellular Membrane; Chronic; Clinical; Clinical Treatment; Defect; Dietary Iron; Disease; Dose; Erythrocytes; Erythropoiesis; Functional disorder; Future; Genetic; Genetic Models; Goals; Guidelines; Hematocrit procedure; Hematology; Hemochromatosis; Hepatotoxicity; Homeostasis; In Vitro; Inflammatory Bowel Diseases; Inherited; Interleukin-10; Ions; Iron; Kidney; Lead; Liver; Liver Microsomes; Mediating; Membrane; Membrane Lipids; Metals; Molecular; Mus; Mutation; National Toxicology Program; Natural Products; Network-based; Organ; Pathogenesis; Pathway interactions; Patients; Physiology; Population; Prosthesis; Proteins; Rattus; Recycling; Rheumatoid Arthritis; Safety; Serum iron level result; Site; Synthesis Chemistry; System; Systemic Lupus Erythematosus; Taiwan; Testing; Therapeutic; Tissues; Toxic effect; Toxicity Tests; Transgenic Mice; Translating; Trees; Turpentine; Venous blood sampling; absorption; base; effective therapy; experimental study; frontier; human disease; in vivo; iron absorption; iron deficiency; loss of function; loss of function mutation; metal transporting protein 1; mouse model; prevent; restoration; side effect; small molecule

1. Project Summary / Abstract This project aims to develop a “molecular prosthetics” approach for treating diseases caused by genetic or acquired deficiencies of the iron transporting protein ferroportin (FPN1), known as Ferroportin disease and Anemia of Inflammation, respectively. Loss of function of FPN1 leads to anemia and/or iron retention in the liver due to deficiencies in the absorption of dietary iron into the blood and/or the recycling of iron from red blood cells. This includes a small population of genetically well-characterized patients with loss-of-function mutations in FPN1, as well as >10 million patients with autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease, Celiac disease, and systemic lupus erythematosus, who suffer from acquired deficiencies of this same protein. Currently available treatments, including regular phlebotomy and blood transfusions fail to address the common underlying deficiency in FPN1 function. Highly collaborative efforts between our labs led to the discovery of a small molecule natural product isolated from the hinoki tree in Taiwan, called hinokitiol, that can autonomously transport iron across cellular membranes. We found that iron gradients build up upstream of the membranes that normally host the missing FPN1 protein, setting the stage for site- and direction-selective restoration of transmembrane iron transport by this inherently not site- and direction-selective small molecule. We also found that that this small molecule iron transporter interfaces with the robust protein-based networks that drive iron homeostasis, creating a molecular bionic-type system. Preliminary results in leading animal models of Ferroportin disease and Anemia of Inflammation are also very encouraging. Building on these frontier concepts and extensive preliminary results, we now plan to probe in depth the effects of genetic and acquired deficiencies of FPN1 in both cells and animals, extensively characterize the capacity for hinokitiol to replicate the function of the missing FPN1 protein and thereby restore physiology, and determine the safety of both acute and chronic administration of hinokitiol. These studies collectively represent a critical next step toward translating this frontier molecular prosthetics approach into a new clinical treatment for patients suffering from diseases caused by FPN1 deficiencies.

1. 项目概要/摘要 该项目旨在开发一种“分子修复术”方法来治疗由遗传引起的疾病 或铁转运蛋白铁转运蛋白 (FPN1) 的获得性缺陷，称为铁转运蛋白病， 分别为炎症性贫血。 FPN1 功能丧失会导致贫血和/或铁潴留 由于膳食铁吸收到血液中和/或从红细胞中回收铁的不足而导致肝脏受损 血细胞。这包括一小部分具有良好遗传特征的功能丧失患者 FPN1 突变，以及超过 1000 万患有自身免疫性疾病（例如类风湿性关节炎）的患者， 患有炎症性肠病、乳糜泻和系统性红斑狼疮的人 这种蛋白质的缺陷。目前可用的治疗方法，包括定期放血和抽血 输血无法解决 FPN1 功能中常见的潜在缺陷。高度协作的努力 我们实验室之间的合作发现了一种从扁柏树中分离出来的小分子天然产物 台湾称为扁柏酚，可以自主地将铁转运穿过细胞膜。我们发现铁 梯度在通常承载缺失 FPN1 蛋白的膜上游形成，奠定了基础 用于跨膜铁运输的位点和方向选择性恢复，这本质上不是位点和方向 方向选择性小分子。我们还发现这种小分子铁转运蛋白与 强大的基于蛋白质的网络可驱动铁稳态，从而创建分子仿生型系统。 铁转运蛋白疾病和炎症性贫血主要动物模型的初步结果也非常好 令人鼓舞。基于这些前沿概念和广泛的初步结果，我们现在计划探索 深入研究 FPN1 遗传性和后天性缺陷对细胞和动物的影响 表征扁柏酚复制缺失 FPN1 蛋白功能并从而恢复的能力 生理学，并确定扁柏酚急性和慢性给药的安全性。这些研究 共同代表了将这一前沿分子修复方法转化为 针对因 FPN1 缺陷引起的疾病的患者的新临床治疗。