权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

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
项目类别：
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

项目摘要

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.