Virus-Receptor Interaction and CYP3A Expression

病毒-受体相互作用和 CYP3A 表达

• 批准号: 6712052
• 负责人: Maria A Croyle
• 金额: $ 10.8万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-05 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6712052
• 关键词: Adenoviridae; antibody neutralization test; cytochrome P450; cytokine; drug metabolism; gene expression; genetic transcription; host organism interaction; immunocytochemistry; integrins; laboratory rat; liver cells; liver metabolism; posttranscriptional RNA processing; posttranslational modifications; protein protein interaction; receptor binding; virus infection mechanism; virus protein; virus receptors; western blottings

DESCRIPTION (provided by applicant): During infection and inflammation, the capacity of the liver to metabolize drugs is impaired due to a reduction in hepatic content of cytochrome P450 (CYP), which can render clinically important medications ineffective or toxic. Cytokines and chemokines contribute as blood borne mediators of this effect on the liver. However, the exact mechanism by which cytokines alter CYP is unknown. Upon infection, viruses take over cellular machinery for self-replication and survival from the time the virus binds to receptors on the cell surface. Integrins, heterodimeric proteins expressed on all nucleated cells, serve as a site of entry for various pathogens. They also initiate signals inside the cell to regulate gene transcription, cell proliferation and survival. Studies of CYP expression in primary cultures of rat and human hepatocytes suggest that integrins influence CYP expression and function. The objective of this study is to investigate mechanisms of long-term virus-induced alterations in drug metabolism, using recombinant adenoviral vectors as prototype pathogens. The hypothesis being tested is that interaction of viral proteins with integrin receptors is responsible for changes of hepatic CYP gene expression and function. Capsid protein effects will be assessed by treating rats with either a "gutted" virus with all viral genes deleted, PEGylated virus which does not interact with integrin receptors, UV inactivated or wild type virus. We will also determine if changes in CYP by these agents is achieved by transcriptional, posttranscriptiontional or postranslational mechanisms in vivo and in macrophage free primary cultures of rat hepatocytes to rule out cytokine effects. This hypothesis has not been tested and could have significant impact on current thought on regulation of CYP gene expression. This is of vast importance as cases of viral infection escalate in the general population and viruses are used as medicinal agents for gene therapy and vaccination protocols. Results from these studies could lead to the development of new anti-viral agents, identification of genetic markers to screen patients for potential aberrations in drug metabolism, and possibly to methods to mitigate drug-induced toxicity during viral infection and design of safer retargeted viruses for therapeutic applications.

描述(申请人提供)：在感染和炎症期间，肝脏代谢药物的能力由于肝脏细胞色素P450(CYP)含量的减少而受损，这可能使临床上重要的药物无效或有毒。细胞因子和趋化因子作为血液传播的媒介对肝脏产生这种影响。然而，细胞因子改变细胞周期蛋白的确切机制尚不清楚。一旦感染，从病毒与细胞表面受体结合的时候起，病毒就接管了自我复制和生存的细胞机制。整合素是在所有有核细胞上表达的异源二聚体蛋白，是各种病原体的进入部位。它们还在细胞内启动信号，以调节基因转录、细胞增殖和生存。对原代培养的大鼠和人肝细胞中CYP表达的研究表明，整合素影响CYP的表达和功能。本研究的目的是以重组腺病毒载体为原型病原体，研究病毒长期诱导药物代谢改变的机制。正在验证的假设是，病毒蛋白与整合素受体的相互作用导致了肝脏CYP基因表达和功能的变化。衣壳蛋白的影响将通过治疗大鼠来评估，方法是用所有病毒基因都被删除的“内脏”病毒、不与整合素受体相互作用的聚乙二醇化病毒、紫外线灭活的或野生型病毒治疗大鼠。我们还将确定这些药物在体内和大鼠肝细胞无巨噬细胞原代培养中是否通过转录、转录后或翻译后机制实现细胞色素P的变化，以排除细胞因子的影响。这一假说尚未得到检验，可能会对目前关于调控CYP基因表达的想法产生重大影响。这一点非常重要，因为病毒感染病例在普通人群中不断升级，病毒被用作基因治疗和疫苗接种方案的药剂。这些研究的结果可能导致新的抗病毒药物的开发，识别遗传标记以筛查患者药物代谢的潜在异常，并可能找到减轻病毒感染期间药物毒性的方法，并设计更安全的重定向病毒用于治疗应用。