Exploiting Notch regulation to probe alternative mechanisms of TSC signalling.

Grant holder: Dr Martin Baron
: University of Manchester

Project status: Ongoing – due to finish 1 Dec 2019.

The normal healthy function of TSC genes is to generate the protein products TSC1 and TSC2, which act in cells to prevent excessive cell division and proliferation. Defective functioning of human TSC genes is associated with a developmental disease that has wide-ranging clinical symptoms, including tumours, seizures and behavioural problems. TSC genes are not just found in humans. Our shared evolutionary history means that TSC genes are found in other organisms as diverse as Fission yeast and Fruit flies. This is fortunate for research into TSC because such genetic model organisms allow us to conduct investigations quickly and easily and in ways that are impossible to do in humans. Indeed studies on the fruit fly have already played an important part in uncovering an important disease mechanism arising from TSC gene misfunction, which results in over-activation of a cellular component called Tor. The latter is an important drug target for TSC, but blocking Tor function is not completely effective in treating all aspects of the disease. Therefore it is an important priority to uncover additional mechanisms by which the TSC genes normally act.

Another, Tor-independent, output of TSC gene function has previously been observed that has placed a role for the TSC genes at a cross roads between signals that establish proper cellular identity and those that control cellular proliferation. In work already undertaken in Manchester, Dr Martin Baron and his team have shown similar Tor-independent links also exist in the cells of the fruit fly, but the detailed mechanisms that mediate these links are not currently understood.

Now Martin's group is returning to the fly model to elucidate the mechanisms linking TSC to developmental signalling pathways, using advanced genetic and cellular biology approaches that make the fly such an effective research tool. If novel mechanisms can be identified then this may provide new targets to develop treatments for individuals whose condition is refractory to Tor inhibitors.


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