Investigation of the translational potential of the ISG15 system for treatment of virus-induced inflammatory cardiomyopathy.

研究 ISG15 系统治疗病毒诱导的炎症性心肌病的转化潜力。

• 批准号: 315301545
• 负责人: Professorin Dr. Antje Beling
• 金额: --
• 依托单位: Fachgebiet Angewandte Biochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/315301545?language=en
• 关键词: Investigation; translational; potential; ISG15; system

Myocarditis is a condition resulting from inflammation of the heart muscle, which in developed countries most commonly results from a viral infection. The course of viral myocarditis is most severe in childhood, with up to 55% mortality in infants. In about 20% of affected patients, acute viral infection triggers chronic inflammatory disease of the heart resulting in cardiac dysfunction with 35% five-year mortality rates. The paramount clinical impact of myocarditis is in contrary to a substantial lack of therapeutic strategies, which target the pathogen and simultaneously manipulate the immune response for the benefit of the host. It has been demonstrated for different pathogens that it is feasible to take advantage of endogenous innate immune effector systems to extend the antiviral therapeutic repertoire. We have recently identified a potent cardiomyocyte-intrinsic defense pathway that acts downstream of such innate responses, which is the Interferon-stimulated gene of 15 kDa (ISG15) protein modification system. ISG15 counteracts viral pathology and preserves immune homeostasis during viral myocarditis, thereby preventing cardiac remodeling, persistence of viral genomes and chronic inflammation. Conjugation of proteins with ISG15 in the heart in particular is needed for preserving survival. In this proposal, we aim to investigate the translational potential of ISG15/ISGylation in a cell-specific manner for heart tissue. The main goal is to target different molecules within the ISG15 protein modification cascade to enhance ISGylation. Therefore, we will implement Adeno-associated virus-induced vector technology and novel in vivo model systems that will eventually enable increased ISG15 expression, stabilization of ISGylated proteins and/or lead to hyper-ISGylation of proteins in heart tissue. Identification of the molecular mechanisms, by which ISG15 limits expansion of viral pathogens in the heart and alleviates detrimental immune responses, will involve ISG15 substrate identification studies by mass spectrometry. The findings of these experiments will guide proof-of-concept experiments that aim for improving disease progression of myocarditis and inflammatory cardiomyopathy in humans. Thereby, both the biochemical analysis of human ISG15 and the application of pluripotent stem cell technology represent critical steps towards the development of suitable therapeutic approaches for high-risk patients in the future.

心肌炎是一种由心肌炎症引起的疾病，在发达国家最常见的是病毒感染。病毒性心肌炎的病程在儿童时期最为严重，婴儿死亡率高达55%。在约20%的受影响患者中，急性病毒感染引发心脏的慢性炎症性疾病，导致心功能障碍，五年死亡率为35%。心肌炎的最重要的临床影响是相反的，大量缺乏治疗策略，靶向病原体，同时操纵免疫反应的主机的利益。对于不同的病原体，已经证明利用内源性先天免疫效应系统来扩展抗病毒治疗谱是可行的。我们最近发现了一种有效的心肌细胞内在防御途径，它作用于这种先天反应的下游，这是干扰素刺激的15 kDa基因（ISG 15）蛋白修饰系统。ISG 15在病毒性心肌炎期间抵消病毒病理并保持免疫稳态，从而防止心脏重塑、病毒基因组的持续存在和慢性炎症。特别是在心脏中，蛋白质与ISG 15的缀合是维持存活所必需的。在这个提议中，我们的目标是研究ISG 15/ISGylation在心脏组织中以细胞特异性方式的翻译潜力。主要目标是靶向ISG 15蛋白修饰级联中的不同分子以增强ISG化。因此，我们将实施腺相关病毒诱导的载体技术和新的体内模型系统，最终能够增加ISG 15表达，稳定ISGylated蛋白和/或导致心脏组织中蛋白质的超ISGylation。ISG 15限制病毒病原体在心脏中的扩张并消除有害免疫应答的分子机制的鉴定将涉及通过质谱法进行的ISG 15底物鉴定研究。这些实验的发现将指导旨在改善人类心肌炎和炎症性心肌病疾病进展的概念验证实验。因此，人ISG 15的生化分析和多能干细胞技术的应用代表了未来为高危患者开发合适治疗方法的关键步骤。