From clinical to molecular characterization of multiple sclerosis

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Background: Multiple sclerosis (MS) is believed to develop in genetic susceptible individuals, triggered by common environmental factors. Characterization of genes and molecular mechanisms involved in disease development is crucial to identify pathogenic pathways, which is the first step towards development of better therapies. Aim: The aim of this study is to identify factors contributing to susceptibility and clinical characteristics of MS in order to establish a better basis for effective treatment. Our first objective is to perform phenotype-genotype analyses of Norwegian and Nordic genome wide association (GWA) screen data, including the relation to cerebrospinal fluid (CSF) findings, as well as selected environmental factors. Our second objective is to perform molecular characterization of selected MS susceptibility genes, here focusing on the C-type lectin domain family 16 member A gene, CLEC16A. Methods: GWA and clinical data from approximately 4000 Nordic MS patients will be analysed with a spe cial focus on CSF findings. Norwegian GWA data will also be analysed in relation to selected enviromental data from 1000 Norwegian MS patients. CLEC16A expression will be analysed both at the mRNA and protein level in blood samples from MS patients and co ntrols, using quantitative real-time PCR and Western blotting. Subcellular localization studies will be performed by fractionation studies and with confocal imaging. To study the CLEC16A function, proliferation, activation and apoptosis will be measured, mainly by flow cytometry based methods, in cells that either overexpress CLEC16A or in cells where CLEC16A is knocked-down (siRNA). Scientific applications: This project is a translational study at the cutting edge of MS research performed by the leading MS genetics group in Norway, involving collaborations with large research networks. The application potential is development of better strategies for treatment of MS.