Tumor-promoting liver injuries and mechanisms

促肿瘤肝损伤及其机制

基本信息

  • 批准号:
    10560586
  • 负责人:
  • 金额:
    $ 49.3万
  • 依托单位:
  • 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

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.
该项目的目标是破译各种肝脏损伤和疾病如何 加速和加剧肝细胞癌(HCC)的发展, 癌症相关死亡率的一半。当前的重点是阐明肿瘤的发生机制, 肝损伤是由肝细胞中的原癌分子的损失产生的。近几 实验中,我们发现Shp 2/Ptpn 11的缺失,以前已知是促癌基因, 二乙基亚硝胺(DEN)或Pten缺乏诱导的HCC发展加重, 纳什与此同时,其他几个研究小组报告说,靶向去除癌蛋白,如 如c-Met、Ikkb和β-catenin,肝细胞中的c-Met、Ikkb和β-catenin确实加重DEN诱导的HCC, 其他致癌驱动因素。然而,其抗肿瘤作用的潜在机制尚不清楚。 这些癌蛋白尚不清楚。我们的假设是原癌分子的丢失 在肝脏微环境中产生多种促肿瘤因子, 加重了肿瘤的发生。值得注意的是,这些小鼠肿瘤模型密切概括了许多 肝癌患者的发病过程。因此,我们认为, 在小鼠模型和人类模型之间共享致癌机制或致癌肝脏疾病。 肿瘤发生和进展的患者。在这个项目上,我们将进行全面的 使用几种方法分析驱动肝癌发生的分子和细胞事件 小鼠模型。我们提出以下三个具体目标:1)寻找和识别 c-Met、Ikkb、Shp 2或b-连环蛋白缺陷的肝脏中的致瘤因子; 2)确定 这些突变体中的突变谱和HCC起始;和3)表征DEN诱导的和 在Shp 2和Ikkb均缺乏的肝脏中自发肿瘤发生。该项目的成功将 破译驱动肝脏肿瘤发生的常见和独特机制,并将促进 设计新的有效的肝癌治疗策略。

项目成果

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Gen-Sheng Feng其他文献

Gen-Sheng Feng的其他文献

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{{ truncateString('Gen-Sheng Feng', 18)}}的其他基金

A new mechanism of hepatocyte proliferation under stress
应激下肝细胞增殖的新机制
  • 批准号:
    10186136
  • 财政年份:
    2021
  • 资助金额:
    $ 49.3万
  • 项目类别:
A new mechanism of hepatocyte proliferation under stress
应激下肝细胞增殖的新机制
  • 批准号:
    10577880
  • 财政年份:
    2021
  • 资助金额:
    $ 49.3万
  • 项目类别:
A new mechanism of hepatocyte proliferation under stress
应激下肝细胞增殖的新机制
  • 批准号:
    10358625
  • 财政年份:
    2021
  • 资助金额:
    $ 49.3万
  • 项目类别:
Project 4: Interrogating and harnessing age-related IFN signaling and innate immunity in HCC prevention and therapy
项目 4:在 HCC 预防和治疗中探究和利用与年龄相关的 IFN 信号传导和先天免疫
  • 批准号:
    10698110
  • 财政年份:
    2021
  • 资助金额:
    $ 49.3万
  • 项目类别:
Project 4: Interrogating and harnessing age-related IFN signaling and innate immunity in HCC prevention and therapy
项目 4:在 HCC 预防和治疗中探究和利用与年龄相关的 IFN 信号传导和先天免疫
  • 批准号:
    10270689
  • 财政年份:
    2021
  • 资助金额:
    $ 49.3万
  • 项目类别:
Intra- and inter-cellular signals that drive hepato-oncogenesis
驱动肝肿瘤发生的细胞内和细胞间信号
  • 批准号:
    10330463
  • 财政年份:
    2020
  • 资助金额:
    $ 49.3万
  • 项目类别:
Tumor-promoting liver injuries and mechanisms
促肿瘤肝损伤及其机制
  • 批准号:
    9887578
  • 财政年份:
    2020
  • 资助金额:
    $ 49.3万
  • 项目类别:
Tumor-promoting liver injuries and mechanisms
促肿瘤肝损伤及其机制
  • 批准号:
    10332735
  • 财政年份:
    2020
  • 资助金额:
    $ 49.3万
  • 项目类别:
Intra- and inter-cellular signals that drive hepato-oncogenesis
驱动肝肿瘤发生的细胞内和细胞间信号
  • 批准号:
    9887833
  • 财政年份:
    2020
  • 资助金额:
    $ 49.3万
  • 项目类别:
Intra- and inter-cellular signals that drive hepato-oncogenesis
驱动肝肿瘤发生的细胞内和细胞间信号
  • 批准号:
    10557925
  • 财政年份:
    2020
  • 资助金额:
    $ 49.3万
  • 项目类别:

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