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

1.项目总结/摘要 该项目旨在开发一种“分子修复学”方法，用于治疗遗传性疾病。 或铁转运蛋白Ferroportin（FPN 1）的获得性缺陷，称为Ferroportin病， 炎症性贫血。FPN 1功能丧失导致贫血和/或铁潴留， 肝脏由于缺乏吸收膳食铁进入血液和/或铁从红细胞再循环 血细胞这包括一小部分遗传特征良好的功能丧失患者 FPN 1突变，以及> 1000万自身免疫性疾病患者，如类风湿性关节炎， 炎症性肠病，乳糜泻和系统性红斑狼疮，谁患有后天性 缺乏相同的蛋白质。目前可用的治疗方法，包括定期抽血和输血 输血不能解决FPN 1功能中常见的潜在缺陷。高度协作的努力 我们的实验室之间的合作导致了一种小分子天然产物的发现，这种产物是从日本扁柏树中分离出来的， 台湾，称为扁柏酚，可以自主运输铁穿过细胞膜。我们发现铁 梯度在通常含有缺失的FPN 1蛋白的细胞膜上游建立， 对于跨膜铁转运的位点和方向选择性恢复， 方向选择性小分子。我们还发现，这种小分子铁转运蛋白与 强大的蛋白质网络驱动铁稳态，创造一个分子仿生型系统。 在膜铁转运蛋白疾病和炎症性贫血的主要动物模型中的初步结果也非常重要。 取得了令人鼓舞在这些前沿概念和广泛的初步结果的基础上，我们现在计划探索 深入研究FPN 1在细胞和动物中的遗传和获得性缺陷的影响， 表征扁柏酚复制缺失的FPN 1蛋白的功能的能力， 生理学，并确定急性和慢性施用扁柏酚的安全性。这些研究 共同代表了将这种前沿分子修复方法转化为 用于患有FPN 1缺陷引起的疾病的患者的新临床治疗。

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.