Tumor-promoting liver injuries and mechanisms
Tumor-promoting liver injuries and mechanisms
批准号:
10332735
负责人:
Gen-Sheng Feng
金额:
$49.3万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-02-20 至 2025-01-31
关键词:
AddressAnimalsAutomobile DrivingCancer EtiologyCarcinogenesis MechanismCellsClinical TreatmentComplementConflict (Psychology)CountryDataDefectDevelopmentDiethylnitrosamineDiseaseDrug TargetingEnvironmental Risk FactorEventExcisionGene MutationGoalsHepatocarcinogenesisHepatocyteHumanIncidenceInflammatory ResponseKnock-outLeadLiverLiver diseasesMalignant - descriptorMalignant neoplasm of liverModelingMolecularMolecular AnalysisMusMutant Strains MiceMutationNFKB Signaling PathwayOncogenicOncoproteinsOutcomePathogenicityPathway interactionsPatientsPrimary Malignant Neoplasm of LiverPrimary carcinoma of the liver cellsProcessRecurrenceReportingRoleSignal TransductionSignaling MoleculeTestingTherapeuticTimeWorkbasebeta catenincarcinogenicitychemical carcinogendesignexperimental studyliver cancer modelliver cancer patientliver cell proliferationliver injurymortalitymouse modelmutantnonalcoholic steatohepatitisnovelnovel therapeutic interventionnovel therapeuticssuccesstheoriestherapeutically effectivetumortumor initiationtumor progressiontumorigenesistumorigenic
中文摘要
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。
英文摘要
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.
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批准号:10186136
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资助金额:$47.24万
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财政年份:2021
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负责人:Gen-Sheng Feng
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依托单位:
A new mechanism of hepatocyte proliferation under stress
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批准号:10577880
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项目类别:
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资助金额:$47.29万
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财政年份:2021
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A new mechanism of hepatocyte proliferation under stress
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批准号:10358625
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项目类别:
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资助金额:$47.29万
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财政年份:2021
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负责人:Gen-Sheng Feng
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依托单位:
Project 4: Interrogating and harnessing age-related IFN signaling and innate immunity in HCC prevention and therapy
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批准号:10698110
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项目类别:
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资助金额:$40.84万
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财政年份:2021
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负责人:Gen-Sheng Feng
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依托单位:
Project 4: Interrogating and harnessing age-related IFN signaling and innate immunity in HCC prevention and therapy
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批准号:10270689
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项目类别:
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资助金额:$37.35万
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财政年份:2021
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负责人:Gen-Sheng Feng
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依托单位:
Intra- and inter-cellular signals that drive hepato-oncogenesis
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批准号:10330463
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项目类别:
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资助金额:$43.38万
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财政年份:2020
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负责人:Gen-Sheng Feng
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依托单位:
Tumor-promoting liver injuries and mechanisms
-
批准号:9887578
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项目类别:
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资助金额:$50.15万
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财政年份:2020
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负责人:Gen-Sheng Feng
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依托单位:
Tumor-promoting liver injuries and mechanisms
-
批准号:10560586
-
项目类别:
-
资助金额:$49.3万
-
财政年份:2020
-
负责人:Gen-Sheng Feng
-
依托单位:
Intra- and inter-cellular signals that drive hepato-oncogenesis
-
批准号:9887833
-
项目类别:
-
资助金额:$42.1万
-
财政年份:2020
-
负责人:Gen-Sheng Feng
-
依托单位:
Intra- and inter-cellular signals that drive hepato-oncogenesis
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批准号:10557925
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项目类别:
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资助金额:$41.38万
-
财政年份:2020
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负责人:Gen-Sheng Feng
-
依托单位:
Dissection of Pten-regulated signals in hepatopathogenesis
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批准号:9033088
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项目类别:
-
资助金额:$35.46万
-
财政年份:2015
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负责人:Gen-Sheng Feng
-
依托单位:
Dissection of Pten-regulated signals in hepatopathogenesis
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批准号:8904285
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项目类别:
-
资助金额:$35.46万
-
财政年份:2015
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负责人:Gen-Sheng Feng
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依托单位:
Shp2 and Pten in Leukemia and Anemia
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批准号:8984713
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项目类别:
-
资助金额:$38.75万
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财政年份:2015
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负责人:Gen-Sheng Feng
-
依托单位:
Molecular and cellular communications in liver tumorigenesis
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批准号:9004608
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项目类别:
-
资助金额:$32.16万
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财政年份:2014
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负责人:Gen-Sheng Feng
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依托单位:
Regulation of Leptin Signaling
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批准号:8046179
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项目类别:
-
资助金额:$5.42万
-
财政年份:2010
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负责人:Gen-Sheng Feng
-
依托单位:
Coordinated regulation of signaling events for insulin biosynthesis and secretion
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批准号:8081319
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项目类别:
-
资助金额:$4.58万
-
财政年份:2010
-
负责人:Gen-Sheng Feng
-
依托单位:
Coordinated regulation of signaling events for insulin biosynthesis and secretion
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批准号:8385568
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项目类别:
-
资助金额:$31.78万
-
财政年份:2009
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负责人:Gen-Sheng Feng
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依托单位:
Coordinated regulation of signaling events for insulin biosynthesis and secretion
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批准号:7759636
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项目类别:
-
资助金额:$36.71万
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财政年份:2009
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负责人:Gen-Sheng Feng
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依托单位:
Tyrosine Dephosphorylation and Blood Cell Development
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批准号:8305554
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项目类别:
-
资助金额:$38.24万
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财政年份:2009
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负责人:Gen-Sheng Feng
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依托单位:
Tyrosine Dephosphorylation and Blood Cell Development
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批准号:8514047
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项目类别:
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资助金额:$36.4万
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财政年份:2009
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负责人:Gen-Sheng Feng
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依托单位:
海外基金