Abstract: In an ageing population, age-associated diseases such as Type-2 Diabetes (T2D) and Osteoarthritis (OA) represent an increasing healthcare and socio-economic burden. Several studies have established that T2D sufferers are more likely to develop OA, suggesting either a causal link or shared risk factors for these diseases. Intriguingly, the post-translational modification, SUMOylation, has been suggested to be involved in both T2D and OA, and studies have demonstrated that exposure of different cell types to T2D dietary risk factors (E.g. saturated fatty acids) increased whole cell protein SUMOylation. Recent genetic association studies have implicated genes involved in the regulation of SELF SUMOylation, such as SENP6, as potential osteoarthritis susceptibility genes but to date we have little understanding of the role they play in the skeletal system. Using zebrafish as an animal model we will test how modulation of SUMOylation affects skeletal cell behaviour in viva and test whether levels of SUMOylation are altered in other mutant lines which develop severe early onset osteoarthritis. We use zebrafish as they develop rapidly, are genetically amenable allowing us to readily generate genetic mutant and are translucent in the larval stages allowing us to follow cell behaviour in the living animal. As zebrafish develop in water, they can readily be drugged by application of compounds of interest to the water in which they are incubated.
In this project the student will use CRISPR-cas9 genome editing to knock out SENP6, they will use live imaging of zebrafish carrying transgenic reporters for chondrocytes, osteoblasts and osteoclasts to visualise the skeletal system. Using biochemical assays (in collaboration with Dr Tim Craig at UWE) they will test levels of SUMOylation in chondrocytes and osteoblasts from wild type and mutant fish at different stages of maturation. Finally using compounds that regulate SUMOlyation we will test whether increasing add/or decreasing levels of SUMOylation can delay osteoarthritis progression in vivo. For more information on the group see www.fishosteoarthritis.com
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