Center for Quantitative Medicine and Department of Cell Biology, University of Connecticut School of Medicine, Farmington, Connecticut, United States of America.
PLoS Comput Biol. 2019 Jan 4;15(1):e1006680. doi: 10.1371/journal.pcbi.1006680. eCollection 2019 Jan.
It is well known that iron is an essential element for life but is toxic when in excess or in certain forms. Accordingly there are many diseases that result directly from either lack or excess of iron. Yet many molecular and physiological aspects of iron regulation have only been discovered recently and others are still elusive. There is still no good quantitative and dynamic description of iron absorption, distribution, storage and mobilization that agrees with the wide array of phenotypes presented in several iron-related diseases. The present work addresses this issue by developing a mathematical model of iron distribution in mice calibrated with ferrokinetic data and subsequently validated against data from mouse models of iron disorders, such as hemochromatosis, β-thalassemia, atransferrinemia and anemia of inflammation. To adequately fit the ferrokinetic data required inclusion of the following mechanisms: a) transferrin-mediated iron delivery to tissues, b) induction of hepcidin by transferrin-bound iron, c) ferroportin-dependent iron export regulated by hepcidin, d) erythropoietin regulation of erythropoiesis, and e) liver uptake of NTBI. The utility of the model to simulate disease interventions was demonstrated by using it to investigate the outcome of different schedules of transferrin treatment in β-thalassemia.
众所周知，铁是生命必需的元素，但过量或在某些形式下会有毒性。因此，有许多疾病直接由铁的缺乏或过量引起。然而，铁调节的许多分子和生理方面最近才被发现，其他方面仍然难以捉摸。目前还没有一个好的定量和动态描述铁的吸收、分布、储存和动员，这与多种铁相关疾病表现出的广泛表型不符。本工作通过开发一个用铁动力学数据校准的小鼠铁分布的数学模型来解决这个问题，然后用铁代谢紊乱的小鼠模型（如血色病、β-地中海贫血、转铁蛋白血症和炎症性贫血）的数据进行验证。为了充分拟合铁动力学数据，需要包括以下机制：a）转铁蛋白介导的铁向组织的输送，b）转铁蛋白结合铁诱导铁调素的产生，c）铁调素调节的依赖于铁蛋白的铁输出，d）促红细胞生成素对红细胞生成的调节，以及 e）未结合铁的肝摄取。通过使用该模型来研究不同转铁蛋白治疗方案在β-地中海贫血中的治疗效果，证明了该模型在模拟疾病干预方面的实用性。
