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.
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