Date of Award

2008

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Professor Timothy Lynch

Second Supervisor

Dr Peter Lynch

Keywords

Multiple Sclerosis, Genetics

Abstract

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).

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

File Size

10,840 KB

Comments

Submitted to the Royal College of Surgeons in Ireland for the degree of Doctor of Philosophy, September 2008.

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