A new humanized mouse model of chronic hepatitis B
A new humanized mouse model of chronic hepatitis B
批准号:
8707714
负责人:
MICHAEL ROBEK
金额:
$20.68万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
已结题
起止时间:
2014-02-12 至 2015-01-31
关键词:
AccountingAcuteAffectAgeAnimalsAntiviral AgentsBiological ModelsCellsCellular biologyChronicChronic Hepatitis BDiseaseEngraftmentGenesGenomeGoalsHematopoieticHepatitis BHepatitis B Core AntigenHepatitis B Surface AntigensHepatitis B VirusHepatitis B e AntigensHepatocyteHumanImmuneImmune responseImmune systemImmunosuppressionImmunotherapeutic agentInfectionInflammationInjection of therapeutic agentKnock-in MouseLeadLengthLiverLiver CirrhosisMaintenanceMalignant neoplasm of liverMethodologyMethodsModelingMouse StrainsMusPathologyPatientsPeripheral Blood Mononuclear CellPhenotypePhysiologicalPlasmidsPopulationPrimary carcinoma of the liver cellsProductionRNAReproducibilityResearchResearch PersonnelRiskSerumSystemT cell responseT-LymphocyteTestingTherapeuticTransgenic MiceVaccinationViral AntigensViremiaVirusVirus Replicationchemokine receptorcytokineexhaustionglobal healthimmunopathologyimprovedin vivoliver infectionliver inflammationliver injurymouse modelnovelpublic health relevancereceptorreconstitutionresponsetraffickingtranscription factorviral DNA
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Chronic hepatitis B virus (HBV) infection is a significant global health problem because it substantially
increases the risk for developing liver cirrhosis and hepatocellular carcinoma. Worldwide, more than 240
million people are chronically infected with HBV, and infection with this virus accounts for ~80% of all liver
cancer. The human immune system can eliminate HBV from the liver, yet often fails to do so, especially in
those who become infected at an early age. HBV persistence is due in part to immunoevasive tactics
employed by the virus as well as host-driven immunosuppression of antiviral immune responses during chronic
infection that serves to limit inflammation and immunopathology. Thus, therapeutic manipulation of the antiviral
T cell response represents a promising method of treatment to cure the infection. However, the lack of suitable
model systems in which to evaluate new immunotherapeutic approaches represents a critical barrier in the
field. The overall goal of this proposal is to develop a new mouse model for HBV that unites the physiological
relevancy of the human immune system with the convenience and reproducibility of genetically defined
transgenic mice. Our general approach will be to combine well-characterized mouse models of HBV replication
with a new strain of "humanized" mice whose immune systems can be efficiently reconstituted with T cells from
HBV-infected patients. We will then test the hypothesis that engraftment of human immune cells in these mice
will lead to an HBV-specific immune response in the liver, and that this response will reflect the disease status
of the human donor. To evaluate our hypothesis, we will carry out two specific aims. First we will introduce
HBV replication into the liver of a mouse strain that contains a number of knock-in gene-humanizations to
improve the engraftment, differentiation, and maintenance of human hematopoietic populations in the animals.
Second, we will engraft these mice with PBMC from acute-resolved and chronic HBV patients, and
characterize how these immune cells traffic to the liver and respond to hepatocytes that produce HBV
antigens. The intent of developing this model system is to provide new means for studying the human HBV
immune responses in vivo. This will fill a critical unmet need, and we anticipate that this system will have wide
application for both basic and translational HBV research to understand T cell functionality in chronic HBV
infection, evaluate novel immunotherapeutic approaches, and identify determinants of HBV
immunopathogenesis. Such analyses could have a substantial impact on the study and treatment of chronic
liver infections in humans.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Human mechanisms of virus persistence in an AAV-based mouse model of chronic HBV infection
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批准号:10057461
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项目类别:
-
资助金额:$49.06万
-
财政年份:2020
-
负责人:MICHAEL ROBEK
-
依托单位:
Human mechanisms of virus persistence in an AAV-based mouse model of chronic HBV infection
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批准号:10391508
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项目类别:
-
资助金额:$49.16万
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财政年份:2020
-
负责人:MICHAEL ROBEK
-
依托单位:
Human mechanisms of virus persistence in an AAV-based mouse model of chronic HBV infection
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批准号:10614465
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项目类别:
-
资助金额:$49.16万
-
财政年份:2020
-
负责人:MICHAEL ROBEK
-
依托单位:
Human mechanisms of virus persistence in an AAV-based mouse model of chronic HBV infection
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批准号:10159211
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项目类别:
-
资助金额:$49.16万
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财政年份:2020
-
负责人:MICHAEL ROBEK
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依托单位:
Enhancing Oncolytic Virotherapy with Type III Interferon
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批准号:8638209
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项目类别:
-
资助金额:$21.14万
-
财政年份:2013
-
负责人:MICHAEL ROBEK
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依托单位:
ENHANCING ONCOLYTIC VIROTHERAPY WITH TYPE III INTERFERON
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批准号:8989222
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项目类别:
-
资助金额:$17.18万
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财政年份:2013
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负责人:MICHAEL ROBEK
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依托单位:
2011 International Meeting on the Molecular Biology of Hepatitis B Viruses
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批准号:8122011
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项目类别:
-
资助金额:$2.0万
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财政年份:2011
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负责人:MICHAEL ROBEK
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依托单位:
Viral Vaccine Vectors to Prevent Hepatocellular Carcinoma
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批准号:7848367
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项目类别:
-
资助金额:$27.29万
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财政年份:2008
-
负责人:MICHAEL ROBEK
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依托单位:
Viral Vaccine Vectors to Prevent Hepatocellular Carcinoma
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批准号:7900191
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项目类别:
-
资助金额:$2.2万
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财政年份:2008
-
负责人:MICHAEL ROBEK
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依托单位:
IL-22 in HBV pathogenesis
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批准号:7742633
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项目类别:
-
资助金额:$18.17万
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财政年份:2008
-
负责人:MICHAEL ROBEK
-
依托单位:
IL-22 in HBV pathogenesis
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批准号:7569274
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项目类别:
-
资助金额:$21.15万
-
财政年份:2008
-
负责人:MICHAEL ROBEK
-
依托单位:
Viral Vaccine Vectors to Prevent Hepatocellular Carcinoma
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批准号:8092019
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项目类别:
-
资助金额:$4.74万
-
财政年份:2008
-
负责人:MICHAEL ROBEK
-
依托单位:
Viral Vaccine Vectors to Prevent Hepatocellular Carcinoma
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批准号:7523399
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项目类别:
-
资助金额:$27.47万
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财政年份:2008
-
负责人:MICHAEL ROBEK
-
依托单位:
Viral Vaccine Vectors to Prevent Hepatocellular Carcinoma
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批准号:8055549
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项目类别:
-
资助金额:$22.91万
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财政年份:2008
-
负责人:MICHAEL ROBEK
-
依托单位:
Viral Vaccine Vectors to Prevent Hepatocellular Carcinoma
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批准号:7678967
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项目类别:
-
资助金额:$26.73万
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财政年份:2008
-
负责人:MICHAEL ROBEK
-
依托单位:
Modulation of HBV Replication by the Immunoproteasome
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批准号:7059460
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项目类别:
-
资助金额:$10.8万
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财政年份:2005
-
负责人:MICHAEL ROBEK
-
依托单位:
Modulation of HBV Replication by the Immunoproteasome
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批准号:6911374
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项目类别:
-
资助金额:$16.0万
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财政年份:2005
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负责人:MICHAEL ROBEK
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依托单位:
Upstate New York Immunology Conference
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批准号:10539665
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项目类别:
-
资助金额:$1.5万
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财政年份:2004
-
负责人:MICHAEL ROBEK
-
依托单位:
Upstate New York Immunology Conference
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批准号:10753116
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项目类别:
-
资助金额:$1.05万
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财政年份:2004
-
负责人:MICHAEL ROBEK
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依托单位:
Molecular Basis of Cytokine-Induced Clearance of HBV DNA
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批准号:6511378
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项目类别:
-
资助金额:$3.83万
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财政年份:2002
-
负责人:MICHAEL ROBEK
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依托单位:
海外基金