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

1.项目摘要/摘要 该项目旨在开发一种“分子假体”方法来治疗由基因引起的疾病。 或获得性铁转运蛋白铁门蛋白(FPN1)缺陷，称为铁门氏病和 分别为炎性贫血。Fpn1功能丧失导致贫血和/或铁滞留 肝脏缺乏对血液中膳食铁的吸收和/或从红色中回收铁 血细胞。这包括一小部分基因特征良好的功能丧失患者。 FPN1基因突变，以及1000万患有自身免疫性疾病的患者，如类风湿性关节炎， 炎症性肠病、腹腔疾病和系统性红斑狼疮，这些人患有获得性 同样的蛋白质的缺陷。目前可用的治疗方法，包括定期抽血和输血 输血未能解决FPN1功能的共同潜在缺陷。高度协作的努力 我们实验室之间的合作导致发现了一种从西诺基树中分离出来的小分子天然产物 台湾的Hinokitiol可以自主地跨细胞膜运送铁。我们发现了那块铁 梯度在通常含有缺失的fpn1蛋白的膜的上游建立，为 对于这个固有的非部位的跨膜铁运输的位置和方向选择性恢复-和 方向选择性小分子。我们还发现，这种小分子铁转运体与 强大的基于蛋白质的网络驱动铁的动态平衡，创造了一个分子仿生型系统。 在主要动物模型中铁转运蛋白疾病和炎症性贫血的初步结果也非常 令人鼓舞。在这些前沿概念和广泛的初步成果的基础上，我们现在计划探索 深入了解fpn1基因缺陷和获得性缺陷对细胞和动物的影响 表征hiokitiol复制缺失的fpn1蛋白的功能从而恢复的能力 生理学研究，并确定急性和慢性给予西诺硫醇的安全性。这些研究 共同代表着将这种前沿分子假体方法转化为 新的临床治疗方法，用于治疗因FPN1缺陷引起的疾病。

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.