Date of Award
PhD (Doctor of Philosophy)
Professor Timothy Lynch
Dr Peter Lynch
Multiple Sclerosis, Genetics
The following thesis tests the working hypothesis that the distinct clinical manifestations of multiple sclerosis (MS) may be underpinned by phenotypespecific differences in gene expression profiles in T-lymphocytes. The first objective of the thesis was to examine in silico gene expression libraries derived from normal brain and MS brain, in order to identify differential gene expression in MS brain lesions. From the cohort of genes identified, genes whose function was likely to be implicated in T-lymphocyte activation were examined in T-lymphocyte preparations from patients with each of the MS phenotypes and healthy controls.
Subsequently, global T-lymphocyte gene expression profiles were compared across MS clinical phenotypes and healthy controls using microarray technology and classification of the major changes in gene expression were made. The expression of a cohort of genes potentially implicated in T-lymphocyte activation were confirmed by real-time RT-PCR and examined in myelin basic protein (MBP)/interleukin-2 stimulated control T-lymphocyte cultures. Lastly, a single nucleotide polymorphism study was carried out in an Irish family with four MS affected siblings, one with secondary progressive MS (SP MS) remainder present with relapsing remitting MS(RR MS).
Overall, the work presented herein demonstrates the utility of a multi-faceted approach to examining gene expression profiles in MS. The data obtained from the in silico studies are robust enough to provide targets which were able to be validated in clinical samples. Elsewhere, microarray comparisons provided interesting evidence pointing to the existence of MS phenotype specific T-lymphocyte activation profiles, at least in terms of the transcriptomic response The family study in conclusion was underpowered in terms of identifying disease loci, but did however demonstrate that there are regions of the genome clearly shared by the affected siblings (281 words).
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Jawad T. A study of the role of genetic factors in the classification of distinct multiple sclerosis clinical phenotypes. [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2008.