Modulation of splicing factor expression by progeroid mutations (360G-Wellcome-207204_Z_17_Z)

Ageing increases physiological frailty; a failure to respond to intracellular and extracellular challenges. In mammals the entry of cells into replicative senescence is now known to be a primary ageing mechanism. Changes in transcripts encoding mRNA splicing regulators have been shown to be associated with age and replicative senescence both in vitro and in vivo. Specifically, in normal human fibroblast cultures, a dramatic shift in alternative isoform usage occurs which we have shown can be reversed by a number of small molecules based upon resveratrol. However, the causal relationship between entry into the senescent state and this shift in isoform use remains unclear as does the universality of splicing factor shifts between individuals. To address the goals of this summer studentship are: (i) to study changes in splicing factor expression in fibroblasts derived from individuals who show accelerated replicative senescence by different kinetic routes. (ii) to study such changes in isogenic telomerase immortalised controls. (iii) to determine if the changes seen at senescence are reversible with resveratrol based modulators of splicing factor expression.