Hepatitis B virus e antigen in viral persistence
Hepatitis B virus e antigen in viral persistence
批准号:
9402258
负责人:
J.-H. James Ou
金额:
$41.25万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-06-20 至 2022-05-31
关键词:
AcuteAdultAffectAntigen ReceptorsCD8-Positive T-LymphocytesCellsCessation of lifeChronicChronic HepatitisChronic Hepatitis BCirrhosisClinicalCore ProteinDevelopmentFemaleGenesGenomic DNAGoalsGrantHepatitis BHepatitis B TherapyHepatitis B e AntigensHepatocyteHorizontal Disease TransmissionHumanImmune ToleranceImmune responseImpairmentInfectionInjectableInjection of therapeutic agentKnowledgeKupffer CellsLeadLengthLifeLiverLiver diseasesMediatingMothersMusMutationNamesNucleotidesPathogenesisPatientsPrimary carcinoma of the liver cellsResearchRiskSymptomsTestingTransgenic MiceVertical Disease TransmissionViralViral GenomeVirusVirus DiseasesVirus Replicationimprovedin uteroin vivomalemouse modelmutantoffspringpathogenpromoterpupreceptorresponseviral DNA
中文摘要
B型肝炎病毒(HBV)可导致严重的肝脏疾病,包括肝硬化和肝细胞癌
(HCC)。世界上大约有3.5亿人长期感染这种病毒,
每年造成50 - 100万人死亡。大多数慢性HBV携带者在生命早期从他们的父母那里获得病毒。
通过垂直传播感染的母亲。相比之下,通过以下途径从其他成人获得HBV的患者,
水平传播通常会发展为自限性急性感染。为什么垂直传播会导致
慢性感染,而水平传播导致自限性急性感染尚不清楚。HBV有一个非常
寄主范围窄,这极大地限制了其研究。我们最近开发了一种小鼠模型,
研究母亲对HBV在后代中持续存在的影响。通过杂交雌性半合子HBV转基因
通过将小鼠转化为雄性幼稚小鼠,我们获得了非转基因小鼠幼崽。当这些非转基因小鼠幼崽
通过流体动力学注射将HBV基因组DNA注射到小鼠体内,HBV复制持续存在
肝脏长达7个月。这与非转基因母亲所生的对照小鼠相反,
HBV DNA注射后3-4周。我们进一步的研究表明,母亲HBV e抗原
HBeAg可调节子代Kupffer细胞,使其发生M2极化以支持HBV
HBeAg再刺激后持续存在。本申请的目的是继续这些先前的研究,
进一步研究HBeAg如何与枯否细胞相互作用。具体来说,我们将确定HBeAg如何刺激
Kupffer细胞,并确定这些细胞中的假定HBeAg受体。我们还将确定HBeAg是否
本身足以调节后代的枯否细胞以支持HBV持续存在,
细胞本身就足以支持HBV的持续存在。我们还将检验HBeAg
条件库普弗细胞在子宫内,以抑制免疫反应的乙肝病毒在后代。最后,我们将研究
HBV基本核心启动子突变体,其具有降低的HBeAg表达,并且与慢性乙型肝炎相关。
乙型肝炎和肝癌风险增加,以测试HBeAg表达的减少是否导致部分
免疫耐受的丧失。建议的研究将为我们了解
HBV垂直传播后持续存在的机制和改善慢性HBV治疗的研究
患者
英文摘要
Hepatitis B virus (HBV) can cause severe liver diseases including cirrhosis and hepatocellular carcinoma
(HCC). There are approximately 350 million people in the world that are chronically infected by this virus,
resulting in 0.5-1 million deaths every year. Most chronic HBV carriers acquired the virus early in life from their
infected mothers through vertical transmission. In contrast, patients who acquired HBV from other adults through
horizontal transmission will usually develop self-limited acute infection. Why vertical transmission leads to
chronic infection whereas horizontal transmission leads to self-limited acute infection is unclear. HBV has a very
narrow host range, which has greatly hampered its research. We have recently developed a mouse model to
study the maternal effect on HBV persistence in the offspring. By crossing female hemizygous HBV transgenic
mice to male naïve mice, we obtained non-transgenic mouse pups. When these non-transgenic mouse pups
were injected with the HBV genomic DNA by hydrodynamic injection, the HBV replication persisted in the mouse
liver for up to seven months. This is in contrast to control mice born to non-transgenic mothers, which cleared
HBV after 3-4 weeks of HBV DNA injection. Our further studies indicated that the maternal HBV e antigen
(HBeAg) could condition the Kupffer cells of the offspring, which would undergo M2 polarization to support HBV
persistence upon re-stimulation by HBeAg. The goal of this application is to continue these previous studies to
further investigate how HBeAg interacts with Kupffer cells. Specifically, we will determine how HBeAg stimulates
Kupffer cells and to identify the putative HBeAg receptor in these cells. We will also determine whether HBeAg
by itself is sufficient to condition Kupffer cells of the offspring to support HBV persistence and whether Kupffer
cells by themselves are sufficient to support HBV persistence. We will also test the hypothesis that HBeAg
conditions Kupffer cells in utero to suppress the immune response to HBV in the offspring. Finally, we will study
the HBV basal core promoter mutant, which has reduced expression of HBeAg and is associated with chronic
hepatitis and an increased risk for HCC, to test whether this reduction of HBeAg expression leads to the partial
loss of immune tolerance. The proposed studies will provide important information for us to understand the
mechanism of HBV persistence after vertical transmission and to improve the treatments for chronic HBV
patients.
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会议论文
Autophagy and the Replication of Hepatitis B Virus
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批准号:10094192
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项目类别:
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资助金额:$41.25万
-
财政年份:2020
-
负责人:J.-H. James Ou
-
依托单位:
Autophagy and the Replication of Hepatitis B Virus
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批准号:10334474
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项目类别:
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资助金额:$41.25万
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财政年份:2020
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负责人:J.-H. James Ou
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依托单位:
Autophagy and the Replication of Hepatitis B Virus
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批准号:10549790
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项目类别:
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资助金额:$41.25万
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财政年份:2020
-
负责人:J.-H. James Ou
-
依托单位:
Hepatitis B virus e antigen in viral persistence
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批准号:10159091
-
项目类别:
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资助金额:$41.25万
-
财政年份:2017
-
负责人:J.-H. James Ou
-
依托单位:
Hepatitis B virus e antigen in viral persistence
-
批准号:10650689
-
项目类别:
-
资助金额:$49.5万
-
财政年份:2017
-
负责人:J.-H. James Ou
-
依托单位:
2014 International Meeting on the Molecular Biology of Hepatitis B Viruses
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批准号:8712000
-
项目类别:
-
资助金额:$0.6万
-
财政年份:2014
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负责人:J.-H. James Ou
-
依托单位:
HBV replication and carcinogenesis
-
批准号:8544645
-
项目类别:
-
资助金额:$20.01万
-
财政年份:2013
-
负责人:J.-H. James Ou
-
依托单位:
HBV replication and persistence in mouse models
-
批准号:8598634
-
项目类别:
-
资助金额:$35.67万
-
财政年份:2013
-
负责人:J.-H. James Ou
-
依托单位:
HBV replication and persistence in mouse models
-
批准号:8719097
-
项目类别:
-
资助金额:$35.77万
-
财政年份:2013
-
负责人:J.-H. James Ou
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依托单位:
HBV replication and carcinogenesis
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批准号:8899467
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项目类别:
-
资助金额:$19.25万
-
财政年份:2013
-
负责人:J.-H. James Ou
-
依托单位:
HBV replication and persistence in mouse models
-
批准号:9068663
-
项目类别:
-
资助金额:$35.89万
-
财政年份:2013
-
负责人:J.-H. James Ou
-
依托单位:
HBV replication and carcinogenesis
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批准号:8721897
-
项目类别:
-
资助金额:$19.05万
-
财政年份:2013
-
负责人:J.-H. James Ou
-
依托单位:
Hepatitis C virus and autophagic response
-
批准号:8250306
-
项目类别:
-
资助金额:$35.54万
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财政年份:2011
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负责人:J.-H. James Ou
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依托单位:
Hepatitis C virus and autophagic response
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批准号:8724487
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项目类别:
-
资助金额:$35.54万
-
财政年份:2011
-
负责人:J.-H. James Ou
-
依托单位:
Hepatitis C virus and autophagic response
-
批准号:8335395
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项目类别:
-
资助金额:$35.54万
-
财政年份:2011
-
负责人:J.-H. James Ou
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依托单位:
Hepatitis C virus and autophagic response
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批准号:8538378
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项目类别:
-
资助金额:$34.3万
-
财政年份:2011
-
负责人:J.-H. James Ou
-
依托单位:
Hepatitis C virus and autophagic response
-
批准号:9325279
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项目类别:
-
资助金额:$37.13万
-
财政年份:2011
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负责人:J.-H. James Ou
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依托单位:
Hepatitis C virus and autophagic response
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批准号:9891047
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项目类别:
-
资助金额:$37.13万
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财政年份:2011
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负责人:J.-H. James Ou
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依托单位:
Hepatitis C virus and intracellular antiviral
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批准号:7746263
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项目类别:
-
资助金额:$27.19万
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财政年份:2009
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负责人:J.-H. James Ou
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依托单位:
Virus-host interactions in hepatocarcinogenesis
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批准号:7847536
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项目类别:
-
资助金额:$108.23万
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财政年份:2007
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负责人:J.-H. James Ou
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依托单位:
海外基金