An integrated computational-experimental approach to identify and optimize combination drug therapy for non-alcoholic fatty liver disease (NAFLD).

非酒精性脂肪性肝病（NAFLD）是最常见的非酒精引起的慢性肝病，全世界有四分之一的人受到影响。20%的NAFLD患者会转变为非酒精性脂肪性肝炎（NASH）。这种疾病的特点是具有生物复杂性，导致症状不仅影响肝脏，而且影响整个生物体，并增加肝硬化、肝细胞癌甚至过早死亡的风险。NASH的单一疗法在多个临床试验中尚未取得成功，主要是由于该疾病的复杂性。因此，不可能实现个体化治疗，因此不同药物的协同组合可能是最好的方法。这种方法可以通过计算-实验方法来实现。目标和药物的几种组合被确定并在计算机上进行测试，其中包括控制工程算法、微流体和荧光显微镜。这将允许对多种药物组合进行深入研究，以确保选择最合适的药物。随后将进行生物分析，以证明计算研究的正确性。同样，为了实现这一目标，需要对肝细胞系进行优化。如果可能的话，这个杰出项目的最后一步将是在体内尝试这种药物组合。更详细地说，该项目的目标是：通过人类肝脏转录谱来表征NAFLD进展的不同阶段。利用药物网络（如Connectivity Map）在计算机上筛选药物组合。优化体外NAFLD人肝细胞模型，用于候选药物的检测。通过将算法与微流控平台相结合来确定最佳药物组合的治疗方法，其中通过荧光显微镜测量细胞系治疗的反应。目的：建立人体精确切肝片平台，用于药物联合研究。此外，由于这是iCASE的学生，还与Galecto Biotech合作。该公司致力于开发针对纤维化、炎症或癌症等多种疾病的新型疗法。他们的研究使这种伙伴关系成为该项目的理想发展伙伴关系。

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease not produced by alcohol, affecting 1 in 4 people worldwide. 20% of the patients that suffer NAFLD, transition to non-alcoholic steatohepatitis (NASH). This disease characterises by having a biological complexity leading to symptoms that affect not only the liver but the whole organism, as well as increasing the risk of liver cirrhosis, hepatocellular carcinoma or even premature death. Single therapy for NASH has not succeed in multiple clinical trials, mostly due to the complexity of the disease. For this reason, it is impossible to reach personalised medicine, hence a synergic combination of different drugs could be the best approach. This approach would be achieved by a computational-experimental methodology. Several combinations of targets and drugs are identified and tested in silico, which would include a control engineering algorithm, microfluidics and fluorescence microscopy. This would allow an intensive study of multiple combinations of drugs to make sure the most suitable ones are chosen. This would be followed by biological assays that would prove the computational studies. Likewise, in order to achieve this, an optimisation of the liver cell line would be needed. The final step of this outstanding project would be, if possible, trying this combination of drugs in vivo too. In more detail this project goals are: To characterize the different stages of NAFLD progression through human hepatic transcriptional profiles. To shortlist in silico drug combinations using drug networks such as Connectivity Map. To optimise an in vitro human liver cellular model of NAFLD for testing the drug candidates. To define the treatment of the best drug combinations by combining algorithms with a microfluidic platform in which the response of the cell line treatment is measured though fluorescence microscopy. To establish a human precision-cut liver slice platform for the study of the drug combinations. Furthermore, as this is an iCASE studentship, there is also a collaboration with Galecto Biotech. This company is involved in the development of novel therapeutics that target multiple diseases that involve fibrosis, inflammation, or cancer. Their studies make this partnership ideal for the development of this project.