Dissection of Pten-regulated signals in hepatopathogenesis

肝病发病机制中 Pten 调节信号的剖析

基本信息

批准号：
9033088
负责人：
Gen-Sheng Feng
金额：
$ 35.46万
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：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9033088
关键词：
1-Phosphatidylinositol 3-Kinase Ablation Address Animal Model Animals Automobile Driving Binding Biochemical Pathway Bioinformatics Breeding Cancer Etiology Cancer Patient Cells Cessation of life Chronic Chronic Hepatitis B Data Defect Development Diagnosis Diethylnitrosamine Disease Dissection Epidemiology Event Excision Gene Mutation Genes Goals Health Hepatic Hepatitis Hepatitis B Virus Hepatitis C Hepatitis C virus Hepatitis Viruses Hepatocarcinogenesis Hepatocyte Hepatomegaly Human Incidence Investigation Kinetics Knockout Mice Liver Liver Cell Adenoma Liver diseases Malignant - descriptor Malignant Neoplasms Malignant neoplasm of liver Modeling Molecular Molecular Profiling Mus Mutant Strains Mice Mutation Neoplasm Transplantation Oncogenes Oncogenic Operative Surgical Procedures PTEN gene Pathogenesis Pathway interactions Patients Penetrance Predisposition Primary Malignant Neoplasm of Liver Primary carcinoma of the liver cells Process Protein Tyrosine Phosphatase Proteins Proto-Oncogene Proteins c-akt Role Signal Pathway Signal Transduction Staging Steatohepatitis Therapeutic Transgenic Animals Transgenic Mice Tumor Suppressor Proteins Viral Virus Virus Diseases Work aged base cancer cell chemical carcinogen curative treatments design hepatopathogenesis leukemia liver transplantation mouse model multidisciplinary neoplastic cell novel novel diagnostics novel therapeutics prevent research study tool transcriptome sequencing tumor tumor initiation tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): It is well known that one gene mutation is not sufficient to trigger tumorigenesis, and therefore one urgent issue is to elucidate how various pro-oncogenic events work cooperatively in driving tumor initiation. Primary liver cancers, in particular hepatocellular carcinoma (HCC), are the 2nd leading cause of cancer-related deaths. Lack of understanding of the molecular pathogenesis for HCC has prevented us from designing mechanism-based therapeutic strategies. Mutations and silencing of Pten tumor suppressor have been detected in many liver cancer patients, but it is unclear how Pten deficiency interacts with other cell signaling disorders in promoting HCC development. Epidemiological analyses clearly indicate a strong association of HCC with chronic hepatitis B or C virus (HBV or HCV) infection in 80% of the diagnosed cases worldwide. However, the majority of hepatitis patients do NOT develop HCCs, indicating requirement of host cell defects in inducing hepato-oncogenesis. In most recent experiments, we found that additional deletion of Shp2 (a tyrosine phosphatase) in hepatocytes dramatically enhanced and accelerated HCC development induced by Pten loss. The Pten and Shp2 double knockout (DKO) mice developed HCCs at 100% penetrance in 7 months. Using this new compound mutant mouse line with defined kinetics of liver tumorigenesis and clear genetic defects, we will determine how Pten deficiency cooperates with additional tumor-promoting events in HCC development. We will also generate new mouse lines by crossing hepatocyte-specific Pten or Shp2 KO mouse with HBV transgenic mouse, to determine the dynamic interplay of viral infection with host cell defects in driving hepatopathogenesis. We will perform RNA-seq and bioinformatics analyses, to understand signaling pathways driving HCC initiation and also tumor cell-intrinsic as well as hepatic environmental signals required for tumorigenesis. We believe that in-depth molecular and cellular analyses of animal tumor models, using multidisciplinary tools, will be a most powerful approach to decipher the mechanisms underlying HCC initiation and progression.

描述（由适用提供）：众所周知，一个基因突变不足以触发肿瘤发生，因此，一个紧迫的问题是阐明各种促疾病的事件在驱动肿瘤倡议方面如何协同起作用。原发性肝癌，尤其是肝细胞癌（HCC），是与癌症相关死亡的第二大主要原因。缺乏对HCC分子发病机理的了解使我们无法设计基于机制的治疗策略。在许多肝癌患者中已经检测到PTEN肿瘤抑制剂的突变和沉默，但是目前尚不清楚PTEN缺乏症如何与其他细胞信号障碍相互作用，以促进HCC发育。流行病学分析清楚地表明，在全球80％的诊断病例中，HCC与慢性丙型肝炎或C病毒（HBV或HCV）感染有很强的关联。然而，大多数肝炎患者不发展HCC，表明宿主细胞缺陷在诱导的肝结合发生中的要求。在最近的实验中，我们发现肝细胞中SHP2（酪氨酸磷酸酶）的其他缺失显着增强和加速了PTEN损失引起的HCC发育。 PTEN和SHP2双基因敲除（DKO）小鼠在7个月内以100％的渗透率开发了HCC。使用这种新的复合突变小鼠系列具有肝肿瘤发生和清晰遗传缺陷的定义动力学，我们将确定PTEN缺乏症如何与HCC发育中的其他肿瘤促进事件合作。我们还将通过将肝细胞特异性PTEN或SHP2 KO小鼠与HBV转基因小鼠交叉生成新的小鼠系，以确定病毒感染与宿主细胞缺陷的动态相互作用，以驱动肝病发生。我们将进行RNA-SEQ和生物信息学分析，以了解驱动HCC倡议的信号通路，以及肿瘤细胞中的肿瘤环境信号。我们认为，使用多学科工具对动物肿瘤模型的深入分子和细胞分析将是一种解读HCC计划和进展的机制的最强大方法。