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Title: RNA-mediated mechanisms of human ageing
Author: Holly , Alice Carole
Awarding Body: Exeter and Plymouth Peninsula Medical School
Current Institution: Exeter and Plymouth Peninsula Medical School
Date of Award: 2013
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Human ageing is a complex deterioration in overall tissue function and is the major risk factor for chronic disease. Understanding the fine-tuning of gene expression may be pivotal in this process. In this thesis, I describe gene expression and the regulation of alternative splicing as a novel mechanism of ageing in man. Gene expression profiles of only five genes can identify individuals predicted to be younger than their chronological age with biologically younger profiles, demonstrating the use of gene expression studies as a biomarker for human ageing. I have identified that alternative splicing is deregulated in human ageing and mRNA transcripts coding for splicing regulators are senescence and age related. Furthermore, gene expression knock-down of Ataxia Telangiectasia Mutated (A TM) indicates a role in the regulation of splicing factors. Our data suggest that global deregulation of splicing factors by a KH-type spl icing regulatory protein (KSRP) or a miRNA-mediated pathway is not likely to be involved in a likely mechanism for A TM-mediated regulation of splicing factors. A subset of microRNAs showed senescence-associated changes in their expression and their age-related putative target genes are involved in many cellular pathways. Finally, I found DNA hypomethylation associated with human ageing within age-associated splicing factors and 53% of the age-related down regulation of SF381 gene expression may be mediated by DNA methylation . I have investigated RNA-mediated mechanisms of human ageing in vivo and in vitro and highlighted the importance of the regulation of gene expression in elucidating the biology of human ageing at the molecular level.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available