BIOMARKERS OF THE THERAPUETIC RESPONSE TO INTERFERON IN MULTIPLE SCLEROSIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 摘要： 该项目旨在确定多发性硬化症患者干扰素治疗反应的分子生物标志物。这一建议是基于这样的假设，即干扰素刺激基因(ISGs)的蛋白产物介导了干扰素在MS患者中的临床效果。该假设是，干扰素刺激基因(ISGs)的诱导在不同的MS患者中是不同的；并且个体对干扰素的分子反应解释了个体对治疗的反应。确定干扰素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，我们希望深入了解一种重要的疾病修改药物在多发性硬化症中的作用机制，并可能了解该病的致病机制。 最近使用高密度微阵列的研究表明，不同的MS患者对干扰素的生物学反应不同。然而，微阵列研究必然局限于少数患者。使用定量聚合酶链式反应(TRAIL)进行的纵向研究也表明个体反应不同，并表明生物学反应与治疗效益相关。使用定制的cDNA微阵列的最新研究记录了对干扰素的反应的个体差异，干扰素具有类似于干扰素的生物效应。体外用干扰素？刺激细胞？ISG调节的模式表现出显著的差异性，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，即从接受干扰素治疗的患者的全血中分离出的RNA，并在没有细胞分离、培养或进一步刺激的情况下进行分析。在干扰素之后，这些大分子阵列的体外调节已被记录在案。丙型肝炎病毒(HCV)患者的治疗(背景部分)和多发性硬化患者的干扰素治疗(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干扰素？的体外反应。在100名RR-MS患者中，他们将在开始干扰素治疗时参加一项纵向研究。干扰素的反应将根据治疗期间的MRI损害进行分类。在治疗期间将监测不良事件。干扰素应答的分子模式将与干扰素应答和不良事件相关。

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.