The role of RIPK1-dependent signaling cues in chronic liver disease and HCC

细胞死亡代表了一种基本的生物学范式，它支配着几乎所有肝脏疾病的预后和长期后遗症。在正常肝脏中，几乎所有的细胞都处于休眠的G0期，几乎没有更新，但在慢性肝病中，这种状态被打乱，病毒、毒性、代谢性或自身免疫性损伤导致肝细胞死亡，随后是炎症和代偿性肝细胞增殖。尽管这些反应确保了急性肝细胞损伤时的有效再生，但慢性肝细胞死亡和相关炎症与纤维化、肝硬化和肝细胞癌（HCC）的发展密切相关。因此，HCC几乎只发生在慢性肝病（CLD）患者中，细胞死亡是这一序列导致癌症的根本驱动因素。在我之前的DFG资助期内产生的研究结果表明，细胞死亡调节剂RIPK1在程序性细胞死亡、代偿性再生、肝脏炎症和肝脏癌变的调节中起着重要作用。此外，我们的数据表明，RIPK1的翻译后修饰可能对其在肝癌发生中作为信号结节的作用至关重要。在这个后续的资助申请中，我们将建立在之前成功的资助期，开创性的初步未发表的发现和我们开发的新的实验工具的基础上，这些工具已经准备好用于本提案，以功能表征可能调节肝癌发生中RIPK1的激活和功能的途径。我们还将系统地分析这些新发现的途径如何影响人类慢性肝病患者肝癌的形成。本研究计划的具体目标是：-评估TBK1/IKKepsilon在肝细胞程序性细胞死亡和细胞死亡反应中的作用-研究TBK1/IKKepsilon在肝损伤和HCC发展中的功能作用及其与TAK1和RIPK1的相互作用-确定肝细胞中Gasdermin D和Gasdermin E的细胞类型特异性功能-研究Gasdermin D和Gasdermin E在TAK1/RIPK1依赖性肝癌发展中的特定功能-通过评估TBK1/IKKepsilon-和Gasdermin D/ e相关信号模块在人类hccop中的预后相关性，我们期望在成功完成这些工作包后，对ripk1依赖性信号提示在肝癌发生中所起的作用建立一个新的和全面的观点。我们还希望发现新的有希望的药物靶向候选药物，可用于慢性肝病患者HCC的风险预测和化学预防策略。

Cell death represents a basic biological paradigm that governs outcomes and long-term sequelae in almost every liver disease. While in the normal liver, almost all cells are in a dormant G0 phase with little turnover, this condition is disturbed in chronic liver disease, where viral, toxic, metabolic or autoimmune injuries result in hepatocellular death, followed by inflammation and compensatory hepatocyte proliferation. Although these responses ensure efficient regeneration in the setting of acute hepatocellular injury, chronic hepatocyte death and the associated inflammation have been closely linked to the development of fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Accordingly, HCC almost exclusively develops in patients with chronic liver disease (CLD), with cell death being the fundamental driver of this sequence leading towards cancer. The findings generated within the previous funding period of my DFG grant implicated that the cell death regulator RIPK1 plays a fundamental role in the regulation of programmed cell death, compensatory regeneration, hepatic inflammation and carcinogenesis in the liver. Moreover, our data suggested that a posttranslational modification of RIPK1 might be crucial for its role as signaling nodule in hepatocarcinogenesis. In this follow up grant proposal, we will build up on the successful previous funding period, groundbreaking preliminary unpublished findings and new experimental tools that we developed and which are ready to use for this proposal to functionally characterize pathways that might modulate the activation and function of RIPK1 in hepatocarcinogenesis. We also will systematically analyze how these newly characterized pathways influence liver cancer formation in human patients with chronic liver disease. The specific objectives of this research proposal are:- Assessing the role of TBK1/IKKepsilon in hepatocyte programmed cell death and cell death responses- Investigating the functional effects of TBK1/IKKepsilon and their interactions with TAK1 and RIPK1 in liver injury and HCC development- Defining the cell-type-specific functions of Gasdermin D and Gasdermin E in hepatocytes- Investigating the specific functions of Gasdermin D and Gasdermin E in TAK1/RIPK1-dependent liver cancer development- Assessing the prognostic relevance of the TBK1/IKKepsilon- and Gasdermin D/E-related signaling modules in human HCCUpon successful completion of these work-packages, we expect to establish a new and comprehensive view on the role played by RIPK1-dependent signaling cues in hepatocarcinogenesis. We also expect to identify novel promising candidates for pharmacological targeting which could be used for risk prediction as well as chemo-preventive strategies against HCC in patients with chronic liver disease.