The role of vitamin D in the pathogenesis and treatment of chronic hepatitis C virus infection

维生素D在慢性丙型肝炎病毒感染发病机制及治疗中的作用

• 批准号: 227608382
• 负责人: Professor Dr. Christian Lange
• 金额: --
• 依托单位: Medizinische Klinik und Poliklinik II - Großhadern
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/227608382?language=en
• 关键词: role; vitamin; pathogenesis; treatment; chronic

Recent clinical evidence suggests a role for vitamin D in the individual responsiveness to interferon-alfa (IFN-alfa)-based therapy of patients with chronic hepatitis C. By searching for the underlying mechanisms, we have identified the inactive vitamin D receptor (VDR) as a novel suppressor of IFN-alfa-induced Jak-STAT signaling in human hepatoma cell lines. The inhibitory impact of VDR was based on a constitutive interaction between the inactive VDR and Stat1, a key molecule in IFN-signal transduction, which was released after stimulation with calcitriol (the bioactive form of vitamin D) and IFN-alfa. As a consequence, calcitriol enhanced the effect of IFN-alfa against hepatitis C virus (HCV) replication in vitro. Implications of this newly identified receptor crosstalk between VDR and IFN-alfa-induced Jak-STAT signaling shall be investigated comprehensively within the here proposed research project. In detail, the impact of calcitriol / the VDR on type II- and III-IFN signaling (IFN-gamma and IFN-lambda) shall be investigated, including a respective in vitro analysis of the possible therapeutic potency of clinical available calcitriol analogues. In addition, the impact of calcitriol / the VDR on IFN signaling in macrophages shall be determined, including an analysis of IFN-dependent antiviral effector functions of macrophages. Finally, a comprehensive transcriptome analysis shall be performed with regard to the influence of the VDR-Stat1 interaction on global gene expression profiles, including potential implications for hepato-carcinogenesis. The results of these analyses may lead to the evaluation of calcitriol and its analogues in IFN-based therapies of various diseases.

最近的临床证据表明，维生素D在慢性丙型肝炎患者对α-干扰素（IFN-α）治疗的个体反应性中发挥作用。通过寻找潜在的机制，我们已经确定了失活的维生素D受体（VDR）作为一种新的抑制IFN-α诱导的Jak-STAT信号在人肝癌细胞系。VDR的抑制作用是基于失活的VDR和Stat 1之间的组成性相互作用，Stat 1是IFN信号转导中的关键分子，在用骨化三醇（维生素D的生物活性形式）和IFN-α刺激后释放。因此，骨化三醇在体外增强IFN-α抗丙型肝炎病毒（HCV）复制的作用。VDR和IFN-alfa诱导的Jak-STAT信号传导之间这种新发现的受体串扰的影响将在本文提议的研究项目中进行全面研究。具体而言，应研究骨化三醇/VDR对II型和III型IFN信号传导（IFN-γ和IFN-λ）的影响，包括对临床可用骨化三醇类似物的可能治疗效力进行相应的体外分析。此外，应确定骨化三醇/VDR对巨噬细胞中IFN信号传导的影响，包括巨噬细胞IFN依赖性抗病毒效应子功能的分析。最后，应就VDR-Stat 1相互作用对全局基因表达谱的影响（包括对肝癌发生的潜在影响）进行全面的转录组分析。这些分析的结果可能导致骨化三醇及其类似物在各种疾病的基于IFN的治疗中的评价。

项目成果

Low Vitamin D Serum Concentration Is Associated With High Levels of Hepatitis B Virus Replication in Chronically Infected Patients

• DOI: 10.1002/hep.26488
• 发表时间: 2013-10-01
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Farnik, Harald;Bojunga, Joerg;Lange, Christian M.
• 通讯作者: Lange, Christian M.