HCV Strain Variation and HCC
HCV 毒株变异与 HCC
基本信息
- 批准号:8115638
- 负责人:
- 金额:$ 22.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-03-09 至 2013-02-28
- 项目状态:已结题
- 来源:
- 关键词:AntibodiesBindingBiologicalBiological MarkersC-terminalCancer EtiologyCell Culture TechniquesCellsChronic Hepatitis CCirrhosisClinicalClinical ResearchCodon NucleotidesCore ProteinDataDevelopmentDiagnostic testsEventExposure toFamilyFutureGene ExpressionGene MutationGenesGoalsHepatitis C AntiviralHepatitis C virusHepatocarcinogenesisHepatocyteIndividualInsulin ResistanceInterferonsInvestigationJapanKineticsLeadLife Cycle StagesLiverLogistic RegressionsLuciferasesMalignant NeoplasmsMalignant neoplasm of liverMeasuresMethodsMolecularMutationN-terminalNested Case-Control StudyOdds RatioOncogenicOutcomePatientsPoint MutationPopulationPrimary carcinoma of the liver cellsProcessProtein BiosynthesisProteinsPublishingRNA replicationReporterResearch PersonnelResistanceRiskSignal PathwaySpecimenSusceptibility GeneTestingTherapeutic InterventionTimeTreatment FailureUnited StatesVariantViralViral PhysiologyViral ProteinsVirulenceVirulentVirusWestern BlottingWestern EuropeWorkbasecarcinogenesisclinically relevantfitnessin vivoinsightmembermetaplastic cell transformationmortalityprimary outcomeprotein expressionresearch studyresponsesecondary outcometumortumorigenesisviral RNAvirus core
项目摘要
DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality in the world. HCV is a major cause of HCC in the United States, Western Europe, and Japan and therefore it is critical to determine the molecular basis of the relationship between HCV and HCC. Published data show that viral point mutations in codons 70 and 91 of the HCV core gene are associated with the development of HCC, interferon (IFN) treatment failure, and insulin resistance. These viral mutations provide a compelling starting point for mechanistic studies of HCV-related hepatocellular carcinogenesis. We recently discovered that these mutations dramatically alter HCV gene expression and control the levels of two previously-unknown HCV proteins, 70 and 91 minicore proteins (Eng et al, 2009, J Virol). The proposed experiments examine the impact of these mutations, and two additional HCC-related HCV mutations that we identified (Fishman et al, 2009, Clin Cancer Res). The goal of Aim I is to determine whether core gene mutations arise prior to the development of liver cancer and thus could potentially promote hepatocellular carcinogenesis. A nested case-control study will be performed to compare core gene sequences of "cases" who developed HCC to those of "controls" who did not develop HCC during the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial. The primary outcome will be the percentage of cases versus controls in which the majority of the variants in the viral RNA population (i.e., the quasispecies) has a codon 70 mutation. Multivariable analysis will be performed to determine whether the codon 70 mutation is an independent predictor of incident HCC. Secondary outcomes will include associations between mutations in other codons and clinical outcomes, and changes in the quasispecies over time. The experimental goal of Aim II is to determine whether the HCC-related mutations confer a survival advantage to HCV during exposure to IFN in cell culture. Viral RNA and protein kinetics will be measured over time by qRT/PCR and Western blotting, using our established methods. These studies will determine the impact of four HCC-related mutations on HCV RNA replica- tion, protein synthesis (including minicore synthesis), and on the ability of HCV to withstand IFN treatment. The in vivo expression of minicores will be confirmed through analysis of liver specimens. This project challenges the paradigm, widely-held by investigators in the United States, that all HCV variants have an equivalent oncogenic potential. Accomplishment of our Aims will fill fundamental gaps in understand- ing the molecular basis of HCV-related oncogenesis and may lead to the identification of new targets for therapeutic interventions and to the development of diagnostic tests for patients harboring oncogenic variants.
PUBLIC HEALTH RELEVANCE: The hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC), the third most common cause of cancer-related mortality in the world. Clinical studies indicate that point mutations in the HCV core gene enhance HCC risk and increase the likelihood of interferon treatment failure. Because of their clinical relevance, we will define the molecular effects of four HCC-associated mutations on viral replication, and also determine whether these mutations arise prior to HCC and therefore warrant investigation as possible biomarkers of virulent strains that can be used to identify patients who have an elevated risk of developing liver cancer.
描述(由申请人提供):肝细胞癌(HCC)是世界上癌症相关死亡的第三大常见原因。 HCV 是美国、西欧和日本 HCC 的主要原因,因此确定 HCV 与 HCC 之间关系的分子基础至关重要。已发表的数据显示,HCV 核心基因密码子 70 和 91 的病毒点突变与 HCC 的发生、干扰素 (IFN) 治疗失败和胰岛素抵抗有关。这些病毒突变为 HCV 相关肝细胞癌变的机制研究提供了令人信服的起点。我们最近发现这些突变显着改变 HCV 基因表达并控制两种以前未知的 HCV 蛋白(70 和 91 微核蛋白)的水平(Eng 等人,2009,J Virol)。拟议的实验检查了这些突变的影响,以及我们发现的另外两种与 HCC 相关的 HCV 突变(Fishman 等,2009,Clin Cancer Res)。目标 I 的目标是确定核心基因突变是否在肝癌发生之前出现,从而可能促进肝细胞癌变。将进行巢式病例对照研究,以比较丙型肝炎抗病毒肝硬化长期治疗 (HALT-C) 试验期间发生 HCC 的“病例”与未发生 HCC 的“对照”的核心基因序列。主要结果将是病毒 RNA 群体(即准种)中大多数变异具有密码子 70 突变的病例与对照的百分比。将进行多变量分析以确定密码子 70 突变是否是 HCC 发生的独立预测因子。次要结果将包括其他密码子突变与临床结果之间的关联,以及准种随时间的变化。 Aim II 的实验目标是确定在细胞培养物中暴露于 IFN 期间,HCC 相关突变是否赋予 HCV 生存优势。将使用我们既定的方法,通过 qRT/PCR 和蛋白质印迹随时间测量病毒 RNA 和蛋白质动力学。这些研究将确定四种 HCC 相关突变对 HCV RNA 复制、蛋白质合成(包括微核合成)以及 HCV 耐受 IFN 治疗能力的影响。微型核心的体内表达将通过肝脏样本的分析来证实。该项目挑战了美国研究人员广泛持有的观念,即所有丙型肝炎病毒变异体都具有同等的致癌潜力。我们目标的实现将填补了解 HCV 相关肿瘤发生的分子基础方面的根本空白,并可能导致治疗干预新靶标的确定以及针对携带致癌变异的患者开发诊断测试。
公共卫生相关性:丙型肝炎病毒 (HCV) 是肝细胞癌 (HCC) 的主要原因,肝细胞癌是世界上癌症相关死亡的第三大常见原因。临床研究表明,HCV 核心基因的点突变会增加 HCC 风险并增加干扰素治疗失败的可能性。由于其临床相关性,我们将定义四种 HCC 相关突变对病毒复制的分子影响,并确定这些突变是否在 HCC 之前出现,因此值得研究作为强毒株的可能生物标志物,可用于识别患有以下疾病的患者:患肝癌的风险较高。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Andrea D. Branch其他文献
Andrea D. Branch的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Andrea D. Branch', 18)}}的其他基金
Genomic and environmental drivers of HCC in Non-Hispanic Blacks: Nature and nurture
非西班牙裔黑人 HCC 的基因组和环境驱动因素:先天和后天
- 批准号:
10856546 - 财政年份:2023
- 资助金额:
$ 22.12万 - 项目类别:
Racial and Ethnic Disparities in Liver Disease in the WTC General Responder Cohort
WTC 一般应答者队列中肝病的种族和民族差异
- 批准号:
10749688 - 财政年份:2023
- 资助金额:
$ 22.12万 - 项目类别:
Evidence of Toxicant-associated Fatty Liver Disease in WTC Responders
世贸中心应急人员中存在与毒物相关的脂肪肝的证据
- 批准号:
10459182 - 财政年份:2021
- 资助金额:
$ 22.12万 - 项目类别:
Evidence of Toxicant-associated Fatty Liver Disease in WTC Responders
世贸中心应急人员中存在与毒物相关的脂肪肝的证据
- 批准号:
10625404 - 财政年份:2021
- 资助金额:
$ 22.12万 - 项目类别:
Evidence of Toxicant-associated Fatty Liver Disease in WTC Responders
世贸中心应急人员中存在与毒物相关的脂肪肝的证据
- 批准号:
10315788 - 财政年份:2021
- 资助金额:
$ 22.12万 - 项目类别:
Hepatotoxic Exposures, Progressive Fatty Liver Disease (NASH), and Liver Cancer Risk in the World Trade Center Health Program General Responder Cohort
世贸中心健康计划一般反应者队列中的肝毒性暴露、进行性脂肪肝 (NASH) 和肝癌风险
- 批准号:
9392829 - 财政年份:2017
- 资助金额:
$ 22.12万 - 项目类别:
Optimizing Vitamin D Treatment in HIV/AIDS: An RCT
优化 HIV/艾滋病维生素 D 治疗:随机对照试验
- 批准号:
8473839 - 财政年份:2010
- 资助金额:
$ 22.12万 - 项目类别:
相似国自然基金
帽结合蛋白(cap binding protein)调控乙烯信号转导的分子机制
- 批准号:
- 批准年份:2021
- 资助金额:58 万元
- 项目类别:
利用分子装订二硫键新策略优化改造α-芋螺毒素的研究
- 批准号:82104024
- 批准年份:2021
- 资助金额:30 万元
- 项目类别:青年科学基金项目
CST蛋白复合体在端粒复制中对端粒酶移除与C链填补调控的分子机制研究
- 批准号:31900521
- 批准年份:2019
- 资助金额:26.0 万元
- 项目类别:青年科学基金项目
Wdr47蛋白在神经元极化中的功能及作用机理的研究
- 批准号:31900503
- 批准年份:2019
- 资助金额:26.0 万元
- 项目类别:青年科学基金项目
ID1 (Inhibitor of DNA binding 1) 在口蹄疫病毒感染中作用机制的研究
- 批准号:31672538
- 批准年份:2016
- 资助金额:62.0 万元
- 项目类别:面上项目
相似海外基金
Strategies for next-generation flavivirus vaccine development
下一代黄病毒疫苗开发策略
- 批准号:
10751480 - 财政年份:2024
- 资助金额:
$ 22.12万 - 项目类别:
Molecular basis of glycan recognition by T and B cells
T 和 B 细胞识别聚糖的分子基础
- 批准号:
10549648 - 财政年份:2023
- 资助金额:
$ 22.12万 - 项目类别:
Decoding AMPK-dependent regulation of DNA methylation in lung cancer
解码肺癌中 DNA 甲基化的 AMPK 依赖性调节
- 批准号:
10537799 - 财政年份:2023
- 资助金额:
$ 22.12万 - 项目类别:
The role of BET proteins in pathological cardiac remodeling
BET蛋白在病理性心脏重塑中的作用
- 批准号:
10538142 - 财政年份:2023
- 资助金额:
$ 22.12万 - 项目类别: