Liver lobule zonation, hepatocellular carcinoma (HCC) and β-catenin mediated hepatitis B virus (HBV) biosynthesis
Liver lobule zonation, hepatocellular carcinoma (HCC) and β-catenin mediated hepatitis B virus (HBV) biosynthesis
批准号:
10059188
负责人:
Alan McLachlan
金额:
$36.58万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-12-01 至 2024-11-30
关键词:
APC geneAcuteAddressAnabolismAnimal ModelAnthelminticsAntiviral AgentsAntiviral TherapyBiological ModelsCapsidCell Culture TechniquesCell LineCellsCessation of lifeChronicChronic Hepatitis BDNA MethylationDNA-Directed DNA PolymeraseDataDevelopmentDrug resistanceEpigenetic ProcessEvaluationFDA approvedGene TargetingGenesGenetic TranscriptionGoalsGrantHealthHepG2Hepatitis B VirusHepatocyteHumanLeadLiverLiver CirrhosisLiver neoplasmsLobuleMalignant neoplasm of liverMediatingMediator of activation proteinMetabolismModalityMolecularMusPI3K/AKTPTEN genePathway interactionsPharmaceutical PreparationsPhenotypePlayPrimary carcinoma of the liver cellsRNARNA-Directed DNA PolymeraseRegulationResolutionReverse Transcriptase InhibitorsReverse TranscriptionRoleSignal TransductionSignal Transduction PathwaySmall Interfering RNATamoxifenTissuesTranscription CoactivatorTransgenic MiceVariantViralViral GenomeViral Load resultVirus DiseasesVirus Replicationbasebeta cateninchronic liver diseasecurative treatmentsdrug developmentgene producthepatoma cellhistone modificationhuman pathogenin vivoinhibitor/antagonistinterestknock-downmanmouse modelmutantnovelpolypeptidetargeted cancer therapytargeted treatmenttherapeutic targettranscription factortumortumor initiation
中文摘要
项目摘要和相关性。
B型肝炎病毒(HBV)感染是一个世界性的健康问题。据估计
世界上有2亿到5亿HBV慢性携带者,迄今为止,
可靠的治疗。HBV引起急性和慢性肝病,
据估计,每年有100万人死于肝硬化和原发性肝细胞癌,
癌(HCC)。目前可用的疗法减少病毒载量,但未能解决
慢性HBV感染,因此需要终身治疗。的主要障碍
慢性HBV感染的解决是合适的HBV靶点数量有限,
抗病毒疗法的发展。目前所有的抗病毒治疗都是针对HBV的
逆转录酶/DNA聚合酶,往往导致耐药的发展
变体。治愈性治疗将需要确定额外的抗病毒靶点。
对HBV生物合成有重要贡献的细胞基因产物代表了
潜在的额外抗病毒靶点,其单独或与当前HBV
逆转录酶抑制剂可能代表一种潜在的治愈疗法。一个潜在
可能代表HBV抗病毒靶点的细胞基因靶点是β-连环蛋白,其末端
Wnt/β-catenin信号转导通路的介导物,其可被
FDA批准的药物,Pyrvinium初步数据表明β-连环蛋白可以被激活,
细胞培养中HBV的转录和复制以及β-连环蛋白活性与病毒感染相关
在慢性病毒感染的HBV转基因小鼠模型中,
因此,将进行细胞培养分析,以确定分子机制
介导β-catenin增强HBV的转录和复制。表征
诱导型肝特异性β-catenin-null和APC-null(β-catenin激活)HBV转基因
小鼠将表明β-连环蛋白对病毒的限制性定位的体内贡献,
生物合成到肝小叶内的中央周围肝细胞,并限制病毒
在HCC组织中表达。此外,治疗HBV复制细胞和
转基因小鼠与Pyrvinium将表明,如果一个可用的FDA批准的药物,
调节Wnt/β-catenin信号转导通路并作为抗病毒治疗。
确定Wnt/β-catenin信号转导通路在决定细胞凋亡水平中的作用
HBV生物合成的研究可能导致细胞治疗靶点的鉴定,
适合于进一步开发新的方式来解决,而不仅仅是治疗
慢性HBV感染
英文摘要
Project Summary and Relevance.
Hepatitis B virus (HBV) infection is a worldwide health problem. It is estimated that there
are 200 to 500 million HBV chronic carriers in the world for whom, to date, there is no
reliable treatment. HBV causes both acute and chronic liver disease and is responsible
for an estimated one million deaths annually from liver cirrhosis and primary hepatocellular
carcinoma (HCC). Currently available therapies reduce viral loads but fail to resolve
chronic HBV infections and hence require lifelong treatment. A major obstacle to the
resolution of chronic HBV infections is the limited number of HBV targets that are suitable
for the development of antiviral therapies. All the current antiviral therapies target the HBV
reverse transcriptase/DNA polymerase, often leading to the development of drug-resistant
variants. Curative therapies will require the identification of additional antiviral targets.
Cellular gene products that make a significant contribution to HBV biosynthesis represent
potential additional antiviral targets which alone or in combination with current HBV
reverse transcriptase inhibitors may represent a potential curative therapy. One potential
cellular gene target that might represent an HBV antiviral target is β-catenin, the terminal
mediator of the Wnt/β-catenin signal transduction pathway which can be inhibited by the
FDA-approved drug, Pyrvinium. Preliminary data indicate that β-catenin can activated
HBV transcription and replication in cell culture and β-catenin activity correlates with viral
biosynthesis in vivo in the HBV transgenic mouse model of chronic viral infection.
Consequently, cell culture analysis will be performed to define the molecular mechanisms
mediating β-catenin enhanced HBV transcription and replication. Characterization of
inducible liver-specific β-catenin-null and APC-null (β-catenin activated) HBV transgenic
mice will indicate the in vivo contribution of β-catenin to the restricted localization of viral
biosynthesis to pericentral hepatocytes within the liver lobule and restricted viral
expression within HCC tissue. Furthermore, treatment of HBV replicating cells and
transgenic mice with Pyrvinium will indicate if an available FDA approved drug can
modulate the Wnt/β-catenin signal transduction pathway and act as an antiviral therapy.
Defining the role of the Wnt/β-catenin signal transduction pathway in determining the level
of HBV biosynthesis may lead to the identification of cellular therapeutic targets that are
amenable to the further development of novel modalities to resolve rather than simply treat
chronic HBV infection.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Developmental regulation of HBV biosynthesis by Ten-eleven translocation (Tet) methylcytosine dioxygenases
-
批准号:10733902
-
项目类别:
-
资助金额:$39.12万
-
财政年份:2023
-
负责人:Alan McLachlan
-
依托单位:
Liver lobule zonation, hepatocellular carcinoma (HCC) and β-catenin mediated hepatitis B virus (HBV) biosynthesis
-
批准号:9884339
-
项目类别:
-
资助金额:$36.58万
-
财政年份:2019
-
负责人:Alan McLachlan
-
依托单位:
Liver lobule zonation, hepatocellular carcinoma (HCC) and β-catenin mediated hepatitis B virus (HBV) biosynthesis
-
批准号:10523111
-
项目类别:
-
资助金额:$35.85万
-
财政年份:2019
-
负责人:Alan McLachlan
-
依托单位:
Liver lobule zonation, hepatocellular carcinoma (HCC) and β-catenin mediated hepatitis B virus (HBV) biosynthesis
-
批准号:10297857
-
项目类别:
-
资助金额:$35.85万
-
财政年份:2019
-
负责人:Alan McLachlan
-
依托单位:
Developmental regulation of HBV biosynthesis by FoxA and DNA methylation
-
批准号:9906839
-
项目类别:
-
资助金额:$39.98万
-
财政年份:2016
-
负责人:Alan McLachlan
-
依托单位:
Developmental regulation of HBV biosynthesis by FoxA and DNA methylation
-
批准号:9275362
-
项目类别:
-
资助金额:$39.98万
-
财政年份:2016
-
负责人:Alan McLachlan
-
依托单位:
Developmental regulation of HBV biosynthesis by FoxA and DNA methylation
-
批准号:9156108
-
项目类别:
-
资助金额:$39.97万
-
财政年份:2016
-
负责人:Alan McLachlan
-
依托单位:
Discovery of novel anti-HBV compounds targeting host factors
-
批准号:8731770
-
项目类别:
-
资助金额:$19.76万
-
财政年份:2013
-
负责人:Alan McLachlan
-
依托单位:
Discovery of novel anti-HBV compounds targeting host factors
-
批准号:8445098
-
项目类别:
-
资助金额:$22.21万
-
财政年份:2013
-
负责人:Alan McLachlan
-
依托单位:
Initiation of Hepatitis B Virus Replication
-
批准号:6771037
-
项目类别:
-
资助金额:$9.39万
-
财政年份:2003
-
负责人:Alan McLachlan
-
依托单位:
Regulation of Hepatitis B Virus Transcription
-
批准号:6572137
-
项目类别:
-
资助金额:$63.34万
-
财政年份:2003
-
负责人:Alan McLachlan
-
依托单位:
Initiation of Hepatitis B Virus Replication
-
批准号:6660195
-
项目类别:
-
资助金额:$9.39万
-
财政年份:2003
-
负责人:Alan McLachlan
-
依托单位:
HEPATITIS B VIRUS
-
批准号:6307373
-
项目类别:
-
资助金额:$2.74万
-
财政年份:1999
-
负责人:Alan McLachlan
-
依托单位:
HEPATITIS B VIRUS
-
批准号:6118081
-
项目类别:
-
资助金额:$2.74万
-
财政年份:1998
-
负责人:Alan McLachlan
-
依托单位:
HEPATITIS B VIRUS
-
批准号:6279276
-
项目类别:
-
资助金额:$2.73万
-
财政年份:1997
-
负责人:Alan McLachlan
-
依托单位:
HEPATITIS B VIRUS
-
批准号:6249228
-
项目类别:
-
资助金额:$2.41万
-
财政年份:1997
-
负责人:Alan McLachlan
-
依托单位:
REGULATION OF HEPATITIS B VIRUS TRANSCRIPTION
-
批准号:2065428
-
项目类别:
-
资助金额:$30.17万
-
财政年份:1991
-
负责人:Alan McLachlan
-
依托单位:
REGULATION OF HEPATITIS B VIRUS TRANSCRIPTION
-
批准号:2837410
-
项目类别:
-
资助金额:$52.64万
-
财政年份:1991
-
负责人:Alan McLachlan
-
依托单位:
REGULATION OF HEPATITIS B VIRUS TRANSCRIPTION
-
批准号:6328700
-
项目类别:
-
资助金额:$55.84万
-
财政年份:1991
-
负责人:Alan McLachlan
-
依托单位:
Regulation of Hepatitis B Virus Transcription
-
批准号:6846320
-
项目类别:
-
资助金额:$9.02万
-
财政年份:1991
-
负责人:Alan McLachlan
-
依托单位:
海外基金