Modeling the pathogenesis of pericentral steatosisInfluence of oxygen on fat accumulation and production of reactive oxygen species

肝移植供体器官的短缺要求延长供体器官标准，以便也可以使用次优器官，如脂肪变性的肝脏，用于肝移植。然而，移植脂肪变性的肝脏伴随着更高的并发症和排斥率。脂肪变性肝脏受到缺血再灌注损伤的影响，这是由于活性氧自由基(ROS)的产生增加所致。ROS的产生程度强烈依赖于脂肪变性肝脏的新陈代谢和氧气供应。在我们的项目中，我们希望通过数学模型来评估ROS产生、脂肪积累和氧气供应之间的关系。在这一过程中，我们将重点放在沿肝血管的代谢分区难以解决的作用，因为它决定了氧气供应的空间安排和低氧的发展。我们将验证分区脂肪堆积发病的一般机制，并揭示脂肪变性肝脏中改变的氧气供应在ROS产生中的作用。该项目旨在提出关于脂肪变性肝脏缺血期间ROS负荷减少的具体假设。这应该通过建模和实验的迭代循环来实现。在第一步中，我们建立了脂肪诱导和酒精诱导的脂肪肝发病机制的肝脏脂肪代谢和ROS产生的模型(常微分方程式)。这里已经实现了肝脏脂肪堆积的单细胞模型(Schleicher等人。2014)将扩展为分区多单元模型。下一步，将利用实验数据对所开发的模型进行标定和验证。对不同参数设置下的模型进行分析，可以评估氧气在脂肪积累和ROS产生中的作用。基于这些结果，我们将提出关于脂肪变性肝脏中ROS产生减少的假设，并在硅胶中进行测试。随后，这些假设将转移到缺血再灌注实验中。最后，该项目将提供工作要点，以提高脂肪变性肝脏对缺血的耐受性。

A shortage of donor organs for liver transplantation demands the extension of donor organ criteria, so that also suboptimal organs, such as steatotic livers, can be used for liver transplantation. However, transplanting steatotic livers is accompanied by an increased rate of complications and rejections. Steatotic livers suffer from ischemia-reperfusion injury due to reinforced production of reactive oxygen species (ROS). The degree of ROS production depends strongly on the metabolism and oxygen supply in the steatotic liver. In our project, we want to evaluate the relationship between ROS production, fat accumulation and oxygen supply by the use of mathematical modeling. In doing so, we focus on the hardly addressed role of metabolic zonation along the hepatic blood vessels, because it determines the spatial arrangement of oxygen supply and the development of hypoxia.We will verify the general mechanisms in the pathogenesis of zonated fat accumulation and uncover the role of the altered oxygen supply in steatotic livers for the production of ROS. The project is aimed to propose specific hypotheses in regard to a reduced ROS burden during ischemia of steatotic livers. This ought to happen through an iterative cycle of modeling and experiments. In a first step, we implement models (ordinary differential equations) of hepatic lipid metabolism and ROS production for the fat-induced and the alcohol-induced fatty liver pathogenesis. Here the already implemented single-cell model of hepatic fat accumulation (Schleicher et al. 2014) will be expanded towards a zonated multi-cell model. In the next step, the developed models will be calibrated and validated by experimental data. The analysis of the models under different parameter sets allows the evaluation of the role of oxygen for fat accumulation and ROS production. Based on the results, we will propose hypotheses in regard to a reduced ROS production in steatotic livers and test them in silico. Subsequently, the hypotheses will be transferred to ischemia-reperfusion experiments. Finally, the project will provide working points to increase the tolerance of steatotic livers to ischemia.