School of Mechanical and Materials Engineering, Washington State University, Pullman, WA 99164-2920, United States.
School of Mechanical and Materials Engineering, Washington State University, Pullman, WA 99164-2920, United States.
Biochim Biophys Acta Gen Subj. 2018 May;1862(5):1168-1179. doi: 10.1016/j.bbagen.2018.02.010. Epub 2018 Feb 18.
Transferrin and its receptors play an important role during the uptake and transcytosis of iron through blood-brain barrier (BBB) endothelial cells (ECs) to maintain iron homeostasis in BBB endothelium and brain. Any disruptions in the cell environment may change the distribution of transferrin receptors on the cell surface, which eventually alter the homeostasis and initiate neurodegenerative disorders. In this paper, we developed a comprehensive mathematical model that considers the necessary kinetics for holo-transferrin internalization and acidification, apo-transferrin recycling, and exocytosis of free iron and transferrin-bound iron through basolateral side of BBB ECs.
Ordinary differential equations are formulated based on the first order reaction kinetics to model the iron transport considering their interactions with transferrin and transferrin receptors. Unknown kinetics rate constants are determined from experimental data by applying a non-linear optimization technique.
Using the estimated kinetic rate constants, the presented model can effectively reproduce the experimental data of iron transports through BBB ECs for many in-vitro studies. Model results also suggest that the BBB ECs can regulate the extent of the two possible iron transport pathways (free and transferrin-bound iron) by controlling the receptor expression, internalization of holo-transferrin-receptor complexes and acidification of holo-transferrin inside the cell endosomes.
The comprehensive mathematical model described here can predict the iron transport through BBB ECs considering various possible routes from blood side to brain side. The model can also predict the transferrin and iron transport behavior in iron-enriched and iron-depleted cells, which has not been addressed in previous work.
转铁蛋白及其受体在血脑屏障（BBB）内皮细胞（EC）摄取和胞吞铁的过程中发挥重要作用，以维持 BBB 内皮细胞和大脑中的铁稳态。细胞环境的任何变化都可能改变细胞表面转铁蛋白受体的分布，最终改变稳态并引发神经退行性疾病。在本文中，我们开发了一个全面的数学模型，该模型考虑了完整转铁蛋白内化和酸化、脱铁转铁蛋白循环以及通过 BBB EC 基底外侧侧铁和转铁蛋白结合铁的胞吐作用的必要动力学。
基于一级反应动力学，我们制定了常微分方程来模拟铁转运，考虑了其与转铁蛋白和转铁蛋白受体的相互作用。通过应用非线性优化技术，从实验数据确定未知动力学速率常数。
使用估计的动力学速率常数，所提出的模型可以有效地再现许多体外研究中通过 BBB EC 的铁转运的实验数据。模型结果还表明，BBB EC 可以通过控制受体表达、完整转铁蛋白-受体复合物的内化和细胞内体中完整转铁蛋白的酸化，调节两种可能的铁转运途径（游离铁和转铁蛋白结合铁）的程度。
本文描述的全面数学模型可以预测铁通过 BBB EC 的转运，同时考虑了从血液侧到大脑侧的各种可能途径。该模型还可以预测铁和转铁蛋白在富含铁和缺铁细胞中的转运行为，这在以前的工作中尚未涉及。
