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

Tumor-promoting liver injuries and mechanisms

促肿瘤肝损伤及其机制

基本信息

批准号：
10332735
负责人：
Gen-Sheng Feng
金额：
$ 49.3万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-20 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10332735
关键词：
Address Animals Automobile Driving Cancer Etiology Carcinogenesis Mechanism Cells Clinical Treatment Complement Conflict (Psychology)Country Data Defect Development Diethylnitrosamine Disease Drug Targeting Environmental Risk Factor Event Excision Gene Mutation Goals Hepatocarcinogenesis Hepatocyte Human Incidence Inflammatory Response Knock-out Lead Liver Liver diseases Malignant - descriptor Malignant neoplasm of liver Modeling Molecular Molecular Analysis Mus Mutant Strains Mice Mutation NFKB Signaling Pathway Oncogenic Oncoproteins Outcome Pathogenicity Pathway interactions Patients Primary Malignant Neoplasm of Liver Primary carcinoma of the liver cells Process Recurrence Reporting Role Signal Transduction Signaling Molecule Testing Therapeutic Time Work base beta catenin carcinogenicity chemical carcinogen design experimental study liver cancer model liver cancer patient liver cell proliferation liver injury mortality mouse model mutant nonalcoholic steatohepatitis novel novel therapeutic intervention novel therapeutics success theories therapeutically effective tumor tumor initiation tumor progression tumorigenesis tumorigenic

项目摘要

The goal of this project is to decipher how various liver injuries and disorders can accelerate and exacerbate development of hepatocellular carcinoma (HCC), one leading cause of cancer-related mortality worldwide. The immediate focus is on elucidating the tumorigenic liver damages generated ironically by loss of pro-oncogenic molecules in hepatocytes. In recent experiments, we found that deletion of Shp2/Ptpn11, previously known to be pro-oncogenic, aggravated HCC development induced by diethylnitrosamine (DEN) or by Pten deficiency and NASH. Consistently, several other groups reported that targeted removal of oncoproteins, such as c-Met, Ikkb, and b-catenin, from hepatocytes indeed aggravated HCC induced by DEN or other oncogenic drivers. However, the underlying mechanisms for the anti-oncogenic effect of these oncoproteins are unclear. Our hypothesis is that loss of the pro-oncogenic molecules generates a variety of tumor-promoting factors in the liver microenvironment, resulting in exacerbated tumorigenesis. Of note, these mouse tumor models closely recapitulate many aspects of the pathogenic process in liver cancer patients. Therefore, we believe that common mechanisms or oncogenic liver disorders are shared between the mouse models and human patients in tumor initiation and progression. On this project, we will pursue a comprehensive analysis of the molecular and cellular events that drive hepato-carcinogenesis using several mouse models. We propose the following three Specific Aims: 1) to search and identify tumorigenic factors in livers deficient for c-Met, Ikkb, Shp2 or b-catenin; 2) to determine the mutation profiles and HCC initiation in these mutants; and 3) to characterize DEN-induced and spontaneous tumorigenesis in liver deficient for both Shp2 and Ikkb. Success of this project will decipher common and distinctive mechanisms that drive liver tumorigenesis, and will facilitate design of novel and effective therapeutic strategies for liver cancer.

Please try later.