Systems Analysis of TNF and TRAIL Signalling Pathways in Hepatocytes

系统水平的理解复杂的生物途径和网络需要了解其单位，结构和时间过程。肝细胞癌（HCC）是世界范围内最常见的癌症之一。HCC由炎症诱导，干扰细胞凋亡的诱导。因此，由于对当前疗法的抗性，HCC的治疗选择受到限制。肿瘤坏死因子（TNF）和肿瘤坏死因子相关凋亡诱导配体（TRAIL）是两种细胞因子，它们在肝细胞中不同地触发炎症和凋亡信号传导。与TNF抑制剂、化疗剂或辐射的共治疗导致主要TRAIL抗性HCC细胞系的TRAIL敏化，而正常分化的肝细胞保持抗性。在Era SysBioPlus联盟中，我们建议研究TNF和TRAIL诱导的炎症和凋亡信号通路在原代和转化肝细胞中的动态调节和阈值，并建立基于拓扑结构的模型来确定通路调节的关键点。我们的小组将完全集中在分析和干扰TNF和TRAIL诱导的信号通路原代人肝细胞。

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.