BIOMARKERS OF THE THERAPUETIC RESPONSE TO INTERFERON IN MULTIPLE SCLEROSIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。摘要：本项目旨在鉴定多发性硬化症患者IFN治疗反应的分子生物标志物。这一建议是基于干扰素刺激基因（ISGs）的蛋白产物介导多发性硬化症患者IFN¿的临床效果的假设。该假设是干扰素刺激基因（ISGs）的诱导在多发性硬化症患者个体中有所不同；个体对干扰素的分子反应解释了个体对治疗的反应。表征IFN -¿治疗反应的分子生物标志物将具有重大的临床影响-该项目的成功完成将为合理的临床决策和临床试验设计提供方法。此外，我们希望能够深入了解一种重要的疾病修饰药物在MS中的作用机制，并可能深入了解该疾病的致病机制。最近使用高密度微阵列的研究表明，对IFN¿的生物学反应在MS患者之间有所不同。然而，微阵列研究必须局限于少数患者。利用TRAIL基因的定量PCR进行的纵向研究也显示了不同的个体反应，并表明生物反应与治疗益处相关。较新的研究使用定制的cDNA大阵列记录了对IFN反应的个体差异，IFN具有与IFN相似的生物效应。体外干扰素刺激细胞？在ISG调节模式上表现出显著的可变性，这取决于细胞的供体来源。这些大阵列已被用于分析体外ISG调节，即从ifn治疗患者的全血中分离RNA，并在不进行细胞分离、培养或进一步刺激的情况下进行分析。体外调节已被记录在IFN？治疗丙型肝炎病毒（HCV）患者（背景部分）和IFN¿治疗多发性硬化症患者（初步数据）。我们将使用由大约250个isg组成的定制基因阵列来研究对IFN的体外反应。在100名RR-MS患者中，他们将在开始IFN治疗时参加一项纵向研究。IFN反应将根据治疗期间的MRI病变进行分类。治疗期间将监测不良事件。干扰素反应的分子模式将与干扰素反应和不良事件相关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT: This project is designed to identify molecular biomarkers of the therapeutic response to IFN in MS patients. This proposal is based on the assumption that protein products of interferon-stimulated genes (ISGs) mediate clinical effects of IFN¿ in patients with MS. The hypothesis is that induction of interferon-stimulated genes (ISGs) varies in individual MS patients; and that the individual molecular response to IFN¿ accounts for the individual response to treatment. Characterizing the molecular biomarkers of therapeutic responses to IFN¿ will have substantial clinical impact - successful completion of this project would provide methods for rational clinical decision-making and clinical trial design. Additionally, we expect to gain insights into the mechanisms of action for an important disease-modifying drug in MS, and may gain insight into pathogenic mechanisms in the disease. Recent studies using high density microarrays demonstrated that the biological responses to IFN¿ varied between MS patients. The microarray studies were necessarily limited to a few patients, however. Longitudinal studies using quantitative PCR of one gene, TRAIL, also indicated variable individual responses, and suggested that the biological response correlated with therapeutic benefit. Newer studies using customized cDNA macroarrays documented individual variability in the response to IFN , which has similar biologic effects as IFN¿. Cells stimulated in vitro with IFN? exhibited remarkable variability in the patterns of ISG regulation, depending on the donor source of the cells. These macroarrays have been tested for analyzing ex vivo ISG regulation, i.e. RNA isolated from whole blood of IFN-treated patients and analyzed without cell isolation, culture or further stimulation. Ex vivo regulation has been documented with these macroarrays following IFN? treatment of patients with hepatitis C virus (HCV) (background section) and IFN¿ treatment of MS patients (preliminary data). We will use customized gene arrays consisting of approximately 250 ISGs to study the ex vivo response to IFN? in 100 patients with RR-MS who will be enrolled in a longitudinal study at the time they initiate IFN¿ therapy. IFN¿ response will be categorized based on MRI lesions while on therapy. Adverse events will be monitored during therapy. Molecular patterns of IFN¿ response will be correlated with IFN¿ response and adverse events.