Control of stellate cells-driven liver cancer by the p62/NBR1 adapters

p62/NBR1 接头控制星状细胞驱动的肝癌

• 批准号: 9891985
• 负责人: Jorge Moscat
• 金额: $ 39.64万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891985
• 关键词: Ablation; Address; Biochemical; Biological Markers; Cells; Cicatrix; Cirrhosis; Comprehension; Data; Data Set; Degradation Pathway; Development; Disease Progression; Epithelial; Epithelium; Fatty Liver; Fibroblasts; Fibrosis; Future; Generations; Goals; Hepatic Stellate Cell; Human; In Vitro; Individual; Inflammation; Inflammatory; Knockout Mice; Link; Liver; Liver diseases; Liver neoplasms; Malignant neoplasm of liver; Molecular; Molecular Mechanisms of Action; Mus; Myofibroblast; Normal tissue morphology; Pathogenesis; Pathology; Pathway interactions; Patients; Play; Prevention; Primary carcinoma of the liver cells; Process; Production; Proteins; Regulation; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Steatohepatitis; Testing; Therapeutic; Transforming Growth Factor beta; Translating; Tumor Suppressor Proteins; base; cancer type; clinically relevant; cohort; effective therapy; experimental study; extracellular; high risk; in vivo; innovation; liver transplantation; mouse model; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; overexpression; patient subsets; prevent; public health relevance; receptor; stellate cell; therapeutic target; trafficking; tumor; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

 DESCRIPTION (provided by applicant): The long-term goal of this proposal is to contribute to the understanding of the molecular signaling mechanisms whereby hepatic stellate cells (HSC) promote hepatocellular carcinoma (HCC) progression. Fibrosis and the inflammatory microenvironment are hallmarks of non-alcoholic steatohepatitis (NASH), and that are increasingly recognized as conducive to cirrhosis, HCC, and end-stage liver disease. This requires liver transplantation, and quite often is the next step in liver disease progression for a significant subset of patients with fatty liver (up to 10 million in the US). Therefore, the identification of the cellular and molecular factors that account for NASH development and how that leads to HCC is a major gap in the understanding of its pathogenesis. Recent results indicate that hepatic stellate cells (HSCs), which differentiate to myofibroblasts upon liver injur and orchestrate the production of extracellular components that form the fibrotic scar and inflammation, are central players in the control of HCC development. This proposal in based on our preliminary in vitro and in vivo studies in mice, and in the analysis of human HCC data sets, strongly suggesting that the signaling adapters p62 and NBR1 are critical players in NASH and HCC development, and that they act by regulating the function and activity of HSCs through a new paradigm involving the negative regulation of TGFβ signaling. Here we will test this hypothesis by addressing the following Aims: (Aim 1) Determine the molecular mechanisms of action of p62 and NBR1 in HSC activation at a cell autonomous level by: (1.1) determining the impact that NBR1 ablation has on TGFβ signaling in HSC activation; and (1.2) unraveling the detailed biochemical links between p62 and NBR1 with different components of the TGFβ signaling cascade. (Aim 2) Determine the contribution of the p62/NBR1 signaling cascade in HSCs to the control of NASH and HCC in cell-specific in vivo mouse models by: (2.1) characterizing HSC-specific knockout mice for p62 and/or NBR1 and determining their contribution to NASH and HCC development; (2.2) determining the signaling pathways altered by p62 and/or NBR1 deficiency in HSCs in vivo; and (2.3) determining the clinical relevance of p62 and NBR1 in HSCs. Results from these studies will serve to identify new biomarkers to predict the NAFLD-NASH- HCC transition, as well as new therapeutic targets for prevention and treatment of these liver pathologies.

 描述（由申请人提供）：该提案的长期目标是有助于理解肝星状细胞（HSC）促进肝细胞癌（HCC）进展的分子信号传导机制和炎症微环境是非肝细胞癌的标志。 -酒精性脂肪性肝炎（NASH），并且越来越多地被认为会导致肝硬化、肝癌和终末期肝病，这需要肝脏。移植，通常是肝病进展的下一步 脂肪肝患者的重要组成部分（在美国高达 1000 万）因此，确定导致 NASH 发展的细胞和分子因素以及如何导致 HCC 是对其发病机制了解的主要空白。结果表明，肝星状细胞（HSC）在肝损伤时分化为肌成纤维细胞，并协调产生形成纤维化疤痕和炎症的细胞外成分，是控制 HCC 发展的核心角色。基于我们对小鼠的初步体外和体内研究以及对人类 HCC 数据集的分析，强烈建议信号转导接头 p62 和 NBR1 在 NASH 和 HCC 发展中发挥关键作用，并且它们通过调节通过 TGFβ 信号传导的负调控新范式来研究 HSC 的功能和活性 在这里，我们将通过解决以下目标来测试这一假设：（目标 1）确定 p62 和 NBR1 在 HSC 中的分子作用机制。通过以下方式在细胞自主水平上激活：(1.1) 确定 NBR1 消除对 HSC 激活中 TGFβ 信号传导的影响；以及 (1.2) 揭示 p62 和 NBR1 与 TGFβ 信号级联的不同成分之间的详细生化联系。 ) 通过以下方法确定 HSC 中 p62/NBR1 信号级联对细胞特异性体内小鼠模型中 NASH 和 HCC 控制的贡献： (2.1) 表征 HSC 特异性敲除小鼠的 p62 和/或 NBR1 并确定其对 NASH 和 HCC 发展的贡献；(2.2) 确定体内 HSC 中 p62 和/或 NBR1 缺陷改变的信号传导途径； p62 和 NBR1 在 HSC 中的临床相关性将有助于确定新的生物标志物来预测 NAFLD-NASH-HCC 转变，以及新的治疗靶点。用于预防和治疗这些肝脏病变。