The systems biology of network stress based on data generated from in vitro differentiated hepatocytes from individual-specific human iPS cells

我们的肝脏是我们身体的主要化学工厂。它从我们的身体中去除不受欢迎的化合物，通常是在化学改变它们之后。这里的情况是，肝脏的这种功能对身体的其他部分有利，但可能对肝脏本身有害：在化学物质的去除过程中，往往会出现有毒化合物，使肝脏承受比去除不受欢迎的化合物的工作量增加所产生的更大的压力。理解肝脏如何应对这种压力的一个主要障碍是人类个体之间的差异。由于这种差异，在一个人身上测量的反应不能用来预测另一个人对压力的反应。个体之间的DNA突变数量有限，但数量可观，其中一些突变会导致体内许多分子的分子功能发生变化。人们不可能将压力反应的差异与任何一种突变分子的差异联系起来。正如在人类社会中一样，活细胞中的过程不是由个人进行的，而是由个人网络进行的。因此，这个项目将试图将个体对压力的反应与他们的分子而不是他们的分子网络联系起来。这将通过将实验与超现代实验方法相结合来完成，例如深度测序和使用快速且编程良好的计算机进行数学建模。其中一个结果将是一个数学模型，它描述了肝脏的部分功能，从而也描述了人体的部分功能。

Our liver is the major chemical factory of our body. It removes unwelcome chemical compounds from our body, often after changing them chemically. The catch 22 situation here is that this function of the liver is good for the rest of the body, but potentially bad for the liver itself: during the chemical removal processes, toxic compounds tend to arise that put the liver under even more stress than already produced by the increased work load of the removal of the unwelcome compounds. A major hurdle in understanding how the liver deals with such stresses, has been the difference between human individuals. Due to this difference the response measured in one individual could not be used to predict the response to the stress in a different individual. Individuals differ in a limited but substantial number of small mutations in their DNA, some of which give rise alterations in molecular function of a number of molecules in the body. It has been impossible to relate differences in the response to stress, back to differences in any one of the mutated molecules. As in human societies, processes in living cells are carried out not by individuals but by networks of individuals. This project will therefore try to relate the response to stress of individuals not to their molecules but to their molecular networks. This will be done by a combination of experimentation with ultra modern experimental methods such as deep sequencing and mathematical modelling using fast and well-programmed computers. One result will be a mathematical model that describes part of the function of the liver and hence of the human.