Hepatitis B Virus X protein and Alcohol Regulation of Cell Cycle Progression

乙型肝炎病毒 X 蛋白和酒精对细胞周期进展的调节

• 批准号: 7545753
• 负责人: Tricia Leigh Gearhart
• 金额: $ 2.73万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545753
• 关键词: Acetaldehyde; Address; Affect; Alcohol consumption; Alcohols; Apoptosis; Apoptotic; Biological Assay; Birds; Cell Cycle; Cell Cycle Progression; Cell Cycle Proteins; Cell Line; Cell Proliferation; Cell Proliferation Regulation; Cells; Chronic; Condition; Development; Ethanol; Ethanol Metabolism; Ethanol toxicity; Event; Exposure to; Family; Generations; Genetic Transcription; Goals; Hepadnaviridae; Hepatitis B Virus; Hepatitis B X-Protein; Hepatocyte; Human; Immune; Individual; Induction of Apoptosis; Infection; Injury; Lead; Liver; Liver Cirrhosis; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Mammals; Mediating; Methods; Molecular; Natural regeneration; Normal Cell; Pathway interactions; Physiology; Primary carcinoma of the liver cells; Proliferating; Proteins; Publishing; Rate; Rattus; Reactive Oxygen Species; Regulation; Reporting; Resistance; Risk Factors; Role; Signal Pathway; Signal Transduction; Simian B disease; Site; System; Thinking; Tissues; Virus; Virus Replication; alcohol effect; alcohol exposure; cell injury; cell transformation; chronic alcohol ingestion; established cell line; hepatotoxin; insight; liver cell proliferation; liver infection; member; prevent; protein expression; prototype; repaired; research study

DESCRIPTION (provided by applicant): The development of hepatocellular carcinoma (HCC), the fifth most common cancer worldwide, is largely associated with known risk factors; common risk factors include chronic infections of the liver with the human hepatitis B virus (HBV) and chronic alcohol consumption. In individuals with both risk factors, there is an increase in the presence of HCC. Understanding how chronic HBV infections and alcohol consumption affect the development of HCC and transformation is important in developing therapies for preventing HBV and alcohol-associated HCC. My application focuses on the effect of the nonstructural, hepatitis B virus X protein (HBx) and alcohol exposure on cell proliferation pathways, how exposure to both agents may exacerbate these effects and the consequence for HBV replication and hepatocyte physiology. We have developed methods for isolating and culturing primary rat hepatocytes, thereby generating a biologically relevant system in which to conduct our studies. We will use this system to address the following specific aims: (1) determine the effects of HBx, HBV and ethanol on cell cycle progression by examining cell proliferation and regulation of cell cycle proteins, (2) we will assay the effect of ethanol exposure and cell cycle progression on HBV replication and explore the roles of specific cell cycle proteins in this relationship and (3) determine how ethanol- and HBx dependent regulation of cellular proliferation pathways impacts hepatocyte apoptosis. The long-term goal of these studies is to generate a mechanistic understanding of the effect of HBx and alcohol on cell proliferation in order to create a better understanding of the signaling pathways activated in the development of HCC. We hypothesize that HBx and alcohol regulation of cell cycle progression will ultimately activate apoptotic pathways in hepatocytes and that, when combined, HBx/HBV and alcohol will cause a greater induction of apoptosis. Alcohol consumption and chronic HBV infection cause a high turnover rate of hepatocytes; this may lead to the eventual selection of hepatocytes resistant to apoptotic signals in a regenerating, diseased liver. The combination of a chronic HBV infection and alcohol consumption causes a more rapid progression of liver injury and HCC development than either ethanol exposure or HBV infection alone. The use of normal hepatocytes provides a more biologically relevant system than similar studies performed in immortalized or transformed cells. Our studies will provide a better understanding of the molecular mechanisms contributing to the development of liver cancer.

描述（由申请人提供）：肝细胞癌（HCC）是全球第五大常见癌症，其发生在很大程度上与已知风险因素相关;常见风险因素包括人类B肝炎病毒（HBV）慢性肝脏感染和慢性饮酒。在具有这两种风险因素的个体中，HCC的存在增加。了解慢性HBV感染和饮酒如何影响HCC的发展和转化，对于开发预防HBV和酒精相关HCC的治疗方法非常重要。我的应用程序的重点是非结构，B肝炎病毒X蛋白（HBx）和酒精暴露对细胞增殖途径的影响，如何暴露于这两种药物可能会加剧这些影响和HBV复制和肝细胞生理学的后果。我们已经开发了分离和培养原代大鼠肝细胞的方法，从而产生了一个生物学相关的系统，在其中进行我们的研究。我们将利用这一系统实现以下具体目标：（1）通过检查细胞增殖和细胞周期蛋白的调节来确定HBx、HBV和乙醇对细胞周期进程的影响，（2）我们将分析乙醇暴露和细胞周期进程对HBV复制的影响，并探索特定细胞周期蛋白在这种关系中的作用;（3）确定乙醇-细胞增殖途径的HBx依赖性调节影响肝细胞凋亡。这些研究的长期目标是对HBx和酒精对细胞增殖的影响产生机制性的理解，以便更好地理解HCC发展中激活的信号通路。我们假设HBx和酒精对细胞周期进程的调节最终将激活肝细胞中的细胞凋亡途径，并且当HBx/HBV和酒精结合时，将导致更大的细胞凋亡诱导。饮酒和慢性HBV感染导致肝细胞的高周转率;这可能导致在再生的患病肝脏中最终选择对凋亡信号具有抗性的肝细胞。慢性HBV感染和饮酒的结合导致肝损伤和HCC发展的进展比单独的乙醇暴露或HBV感染更快。正常肝细胞的使用提供了一个比在永生化或转化细胞中进行的类似研究更具生物学相关性的系统。我们的研究将有助于更好地了解肝癌发展的分子机制。