Study of the ageing-related pre-mRNA splicing of the LMNA gene
Precursor messenger RNA (pre-mRNA) splicing is a cellular process in which non-coding sequences (introns) are removed and coding sequences (exons) are joined together to generate mRNA for protein production. Splicing is somewhat similar to film editing: if it is not done properly, two unmatched scenes may be stitched together in one episode, which would not make sense. In splicing, if exon-intron boundaries (splice sites) are not correctly identified, the wrong mRNA will be produced from which a faulty protein will be synthesised causing disease. The premature ageing disease, Hutchinson Gilford Progeria Syndrome (HGPS), originates from the mutation in exon 11 of the LMNA gene that creates a splice site which is then mistakenly used leading to production of the truncated protein, named progerin. Small amount of progerin was detected in healthy people raising the hypothesis that, with ageing, the progerin splice site is more often used triggering physiological changes that make us older.
The goal of the project is to identify the proteins that play a key role in modulating the splicing outcomes of two alternative splicing events: (i) aberrant production of progerin, causing HGPS, and (ii) alternative LMNA splicing generating lamin A and C proteins that have partially overlapping functions. Since progerin can be only produced from the pre-mRNA encoding lamin A protein, an ability to force a splicing outcome in favour to lamin C over lamin A can be potentially employed to decrease the amount of progerin. Since the proteins modulating these specific splicing outcomes are likely to affect the speed of the ageing process, the pharmaceutical targeting of these proteins - inhibition of their function by small interacting molecules -- may lead to the discovery of novel drugs capable of slowing the ageing process. Methods: DNA cloning, tissue culture transfections; in vitro pre-mRNA splicing; RNA-protein interactions; real-time PCR.
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