Systems Analysis of TNF and TRAIL Signalling Pathways in Hepatocytes

系统级理解复杂的生物途径和网络需要其单位，结构和时间过程的知识。肝细胞癌（HCC）是世界上最常见的癌症之一。肝细胞癌是由炎症诱导的，干扰细胞凋亡的诱导。因此，由于对现有疗法的耐药性，HCC的治疗选择有限。肿瘤坏死因子（tumor necrosis factor， TNF）和与TNF相关的凋亡诱导配体（apoptosis-inducing ligand， TRAIL）是肝细胞中两种不同的触发炎症和凋亡信号的细胞因子。与TNF抑制剂、化疗药物或照射共同治疗可导致TRAIL致敏，主要是TRAIL耐药的HCC细胞系，而正常分化的肝细胞仍具有耐药性。在Era SysBioPlus联盟中，我们建议研究原代和转化肝细胞中TNF-和trail诱导的炎症和凋亡信号通路的动态调节和阈值，并建立基于拓扑的模型来确定通路调节的关键点。我们的团队将完全专注于分析和干扰TNF-和trail诱导的原发性人肝细胞信号通路。

Systems level understanding of complex biological pathways and networks requires knowledge of its units, structures and temporal processes. Hepatocellular carcinoma (HCC) is one of the commonest cancers world-wide. HCC is induced by inflammation, interfering with induction of apoptosis. As a result, therapeutic options for HCC are limited due to resistance to current therapies. Tumour necrosis factor (TNF) and the TNF-related apoptosis-inducing ligand (TRAIL) are two cytokines which differentially trigger inflammatory and apoptotic signalling in liver cells. Co-treatment with inhibitors of TNF, chemotherapeutic agents or irradiation results in TRAIL sensitisation of primarily TRAIL-resistant HCC cell lines whereas normally differentiated hepatocytes remain resistant. Within the Era SysBioPlus consortium we propose to investigate the dynamic regulation and threshold of TNF- and TRAIL-induced inflammatory and apoptotic signalling pathways in primary and transformed hepatocytes and to build topology-based models to identify critical points for pathway regulation. Our group will focus entirely on the analysis and perturbation of TNF- and TRAIL-induced signalling pathways primary human hepatocytes.