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

基本信息

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
项目类别：
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

项目摘要

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。项目摘要 /摘要该项目旨在开发一种“分子假肢”方法来治疗由遗传引起的疾病或获得的铁运输蛋白铁蛋白（FPN1）的缺陷，称为铁托蛋白疾病和炎症的贫血。 FPN1功能的丧失导致贫血和/或铁的保留率由于饮食中铁荒谬而引起的肝脏引起的肝脏和/或红色的铁回收血细胞。这包括少数一般特征良好的患者，功能丧失 FPN1的突变以及> 1000万自身免疫性疾病的患者，例如类风湿关节炎，炎症性肠病，乳糜泻和全身性红斑狼疮，他们因获得相同蛋白质的缺乏。目前可用的治疗方法，包括定期的静脉曲张和血液输血无法解决FPN1功能中常见的潜在缺陷。高度协作的努力在我们的实验室之间，发现了从Hinoki树中隔离的小分子天然产物台湾，称为Hinokitiol，可以自主在细胞膜上自动运输铁。我们发现铁梯度在通常容纳缺失的FPN1蛋白的膜的上游积聚，设置了舞台用于跨膜铁运输的位点和方向选择性恢复本质上不是位点和方向选择性小分子。我们还发现，这种小分子铁转运蛋白与稳健的基于蛋白质的网络驱动铁稳态，从而产生分子仿生型系统。在领先的亚铁蛋白疾病和炎症贫血的动物模型中，初步结果也非常鼓励。以这些边界概念和广泛的初步结果为基础，我们现在计划调查深度在细胞和动物中遗传和获得的FPN1缺乏的影响，广泛表征Hinokitiol复制缺失FPN1蛋白功能的能力，从而恢复生理学，并确定急性和慢性给药的安全性。这些研究集体代表着将这种前沿分子假体方法转化为一个关键的下一步针对由FPN1缺陷引起的疾病患者的新临床治疗。