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

RIPK1 依赖性信号传导在慢性肝病和 HCC 中的作用

• 批准号: 279874820
• 负责人: Professor Dr. Tom Lüdde, Ph.D.
• 金额: --
• 依托单位: Klinik für Gastroenterologie, Hepatologie und Infektiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/279874820?language=en
• 关键词: role; RIPK1; dependent; signaling; cues

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this follow up grant proposal, we will build up on the successful previous funding period, groundbreaking preliminary unpublished findings and new experimental tools that we developed and which are ready to use for this proposal to functionally characterize pathways that might modulate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.

细胞死亡代表了一种基本的生物学范式，它支配着几乎每一种肝病的结果和长期后遗症。在正常肝脏中，几乎所有的细胞都处于休眠的G0期，周转率很低，而在慢性肝病中，这种情况会受到干扰，病毒、毒性、代谢或自身免疫损伤会导致肝细胞死亡，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的有效再生，但慢性肝细胞死亡和相关的炎症与纤维化、肝硬变和肝细胞癌的发展密切相关。因此，肝细胞癌几乎只发生在慢性肝病(CLD)患者中，细胞死亡是导致癌症的这个序列的根本驱动因素。在我的DFG赠款的前一个资助期内产生的研究结果表明，细胞死亡调节因子RIPK1在调节细胞程序性死亡、代偿性再生、肝脏炎症和肝脏癌变方面发挥着重要作用。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。在这项后续拨款提案中，我们将在之前成功的资助期、突破性的未发表的初步发现和新的实验工具的基础上，开发并准备用于这项提案，以从功能上表征可能调节RIPK1在肝癌发生中的激活和功能的途径。我们还将系统地分析这些新表征的途径如何影响人类慢性肝病患者的肝癌形成。本研究方案的具体目标是：-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-调查TBK1/IKKepsilon在肝损伤和肝细胞癌发展中的功能效应及其与TAK1和RIPK1的相互作用-确定Gasdermin D和Gasdermin E在肝细胞中特定细胞类型的功能-调查Gasdermin D和Gasdermin E在依赖于TAK1/RIPK1的肝癌发展中的特定功能-评估与预后相关的TBK1/IKKepsilon和Gasdermin D/E信号模块在人肝癌中的相关性我们期望对RIPK1依赖的信号通路在肝癌发生中所起的作用建立一个新的、全面的观点。我们还期望找到新的有希望的药物靶向候选药物，用于慢性肝病患者的风险预测和肝细胞癌的化学预防策略。