Hepatitis B virus X protein modulation of calcium signaling in HCC development
乙型肝炎病毒 X 蛋白对 HCC 发展中钙信号的调节
基本信息
- 批准号:8397853
- 负责人:
- 金额:$ 4.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-08-01 至 2015-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectApoptosisAreaBiological ModelsCa(2+)-Calmodulin Dependent Protein KinaseCalcineurinCalciumCalcium SignalingCalmodulinCalmodulin-Binding ProteinsCancer EtiologyCancer ModelCell CycleCell LineCell ProliferationCell Proliferation RegulationCell physiologyCellsCessation of lifeChronicChronic Hepatitis BCouplesCyclic AMP-Responsive DNA-Binding ProteinCyclin D1Cyclin ECytosolDevelopmentDistalEnvironmentEventExposure toGenomeGoalsHepatitis BHepatitis B IncidenceHepatitis B VirusHepatitis B X-ProteinHepatoblastomaHepatocarcinogenesisHepatocyteHumanImmuneIndividualInfectionInfectious AgentInvestigationKineticsLinkLiver RegenerationMalignant NeoplasmsMalignant neoplasm of liverMediatingMethodsMonitorMusNeoplasm MetastasisNormal CellPathway interactionsPhysiologyPlayPrimary carcinoma of the liver cellsProcessProteinsRattusRegulationRodentRoleSignal TransductionSignal Transduction PathwayToxinTransgenic MiceTransgenic OrganismsViral ProteinsVirus DiseasesVirus Replicationactivating transcription factorc-myc Genescancer initiationcell typeextracellularmortalitymouse modelnew therapeutic targetnovelnuclear factors of activated T-cellsprotein activationprotein expressiontumor
项目摘要
DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and third highest cause of cancer-related deaths. Although the development of HCC has been linked to exposure to various toxins or infectious agents, the majority of HCC cases are associated with chronic hepatitis B virus (HBV) infections. Worldwide, there are over 350 million people chronically infected with HBV, and approximately 25 percent of these individuals will eventually develop HCC. The high incidence of HBV infections, the high mortality rate of individuals with HCC, the increasing occurrence of HCC, and the strong association between chronic HBV infections and HCC development indicates that investigating the mechanisms underlying the development of HBV-associated HCC is a critically important area of investigation. While not entirely understood, these underlying mechanisms are thought to involve the immune-mediated destruction of HBV-infected hepatocytes and compensatory liver regeneration as well as activities of the multifunctional HBV X protein (HBx). HBx has been shown to be required for HBV replication and is thought to play at least a co-factor role in HCC development. Ca2+ signaling influences almost every cellular process and has been shown to play a critical role in many aspects of cancer development; the Ca2+-binding protein calmodulin (CaM) is thought to be a major contributor to cancer development and is required for cell proliferation. Interestingly, HBx regulation of Ca2+ signals is thought to act as an upstream initiating event for many other HBx effects, and Ca2+ has been shown to be required for HBx regulation of cell proliferation, apoptosis and HBV replication. We hypothesize that HBx modulates store-operated Ca2+ (SOC) entry (SOCE) to increase cytosolic Ca2+ levels and stimulate HBV replication, while consequently de-regulating normal hepatocyte Ca2+ signaling to increase CaM activation and CaM-dependent modulation of cell proliferation. The goal of this application is to define the effect of HBx on SOCE in cultured primary rodent hepatocytes, a biologically relevant model system, and how this regulation affects HBV replication, CaM signaling, and CaM-mediated cell proliferation. In Aim 1, we will investigate HBx regulation of SOCE using kinetic Ca2+ studies. We will also determine the impact of HBx on expression levels of SOC channel components and how this affects HBV replication. In Aim 2, we will investigate additional consequences of HBx regulation of Ca2+ by analyzing the impact of HBx on CaM signaling and CaM regulation of cell proliferation. In Aim 3, we will address the significance of HBx regulation of SOCE and CaM signaling for HCC development by utilizing an HBx-transgenic mouse liver cancer model; we will disrupt SOCE and CaM in these mice and determine the impact on HCC development. Overall, we expect that our studies will identify mechanisms by which HBx alters hepatocyte physiology to promote HBV replication and HCC development. Our studies may also identify new therapeutic targets for blocking HBx activities and HBV replication and the development of HBV-associated HCC.
PUBLIC HEALTH RELEVANCE: The Hepatitis B Virus (HBV) HBx protein modulates hepatocyte calcium signaling to stimulate HBV replication. Persistent HBV replication has been linked to the development of hepatocellular carcinoma (HCC). We will use cultured primary rat hepatocytes and HBx-transgenic mice to characterize HBx modulation of calcium signaling and elucidate novel HBx activities that alter hepatocyte physiology, regulate HBV replication, and could contribute to the development of HCC.
描述(申请人提供):肝细胞癌是全球第六大常见癌症,也是癌症相关死亡的第三大原因。虽然肝细胞癌的发生与暴露于各种毒素或感染剂有关,但大多数肝细胞癌病例与慢性乙型肝炎病毒(HBV)感染有关。在世界范围内,有超过3.5亿人慢性感染乙肝病毒,其中约25%的人最终将患上肝细胞癌。乙肝病毒感染的高发病率、肝细胞癌患者的高死亡率、肝细胞癌发病率的增加以及慢性乙肝病毒感染与肝细胞癌发生发展之间的密切联系表明,研究乙肝病毒相关性肝细胞癌的发生机制是一个极其重要的研究领域。虽然还不完全清楚,但这些潜在的机制被认为涉及免疫介导的乙肝病毒感染的肝细胞的破坏和代偿性肝再生以及多功能HBVX蛋白(HBx)的活性。HBx已被证明是乙肝病毒复制所必需的,并被认为至少在肝细胞癌的发生中起辅助因素的作用。钙信号影响几乎每一个细胞过程,并已被证明在癌症发生的许多方面发挥关键作用;钙结合蛋白钙调蛋白(CaM)被认为是癌症发生的主要贡献者,是细胞增殖所必需的。有趣的是,HBx对Ca~(2+)信号的调节被认为是许多其他HBx效应的上游启动事件,而且已经证明HBx对细胞增殖、凋亡和乙肝病毒复制的调节是必需的。我们假设HBx通过调节细胞内钙离子进入(SOCE)来增加细胞内钙离子水平,刺激病毒复制,同时去调节正常肝细胞钙信号从而增加CaM的激活和细胞增殖的CaM依赖的调节。这项应用的目的是确定HBx对原代培养的啮齿动物肝细胞SOCE的影响,以及这种调控如何影响乙肝病毒复制、CaM信号转导和CaM介导的细胞增殖。在目标1中,我们将通过动态钙离子研究来研究HBx对SOCE的调控。我们还将确定HBX对SOC通道组件表达水平的影响,以及这如何影响乙肝病毒复制。在目标2中,我们将通过分析HBx对CaM信号和CaM调节细胞增殖的影响来研究HBx调节钙离子的其他后果。在目标3中,我们将利用HBx转基因小鼠肝癌模型来研究HBx对SOCE和CaM信号的调节在肝癌发生中的意义;我们将在这些小鼠中干扰SOCE和CaM信号,并确定其对肝癌发生的影响。总体而言,我们预计我们的研究将确定HBx改变肝细胞生理以促进乙肝病毒复制和肝细胞癌发生的机制。我们的研究还可能确定新的治疗靶点,以阻断HBx活性和乙肝病毒复制,并发展与乙肝病毒相关的肝细胞癌。
与公共健康相关:乙肝病毒(乙肝)HBx蛋白调节肝细胞钙信号以刺激乙肝病毒复制。乙肝病毒的持续复制与肝细胞癌的发生有关。我们将利用培养的大鼠原代肝细胞和HBx转基因小鼠来研究HBx对钙信号的调控,并阐明新的HBx活性,这些活性可以改变肝细胞的生理,调节乙肝病毒的复制,并可能有助于肝细胞癌的发展。
项目成果
期刊论文数量(0)
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Jessica Casciano其他文献
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{{ truncateString('Jessica Casciano', 18)}}的其他基金
Hepatitis B virus X protein modulation of calcium signaling in HCC development
乙型肝炎病毒 X 蛋白对 HCC 发展中钙信号的调节
- 批准号:
8536585 - 财政年份:2012
- 资助金额:
$ 4.02万 - 项目类别:
Hepatitis B virus X protein modulation of calcium signaling in HCC development
乙型肝炎病毒 X 蛋白对 HCC 发展中钙信号的调节
- 批准号:
8703045 - 财政年份:2012
- 资助金额:
$ 4.02万 - 项目类别:
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