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Understanding mechanisms of Notch regulation and misregulation in endocytic pathway


Project Description

Notch is a developmental signalling receptor with widespread and important roles in metazoan development and also in adult stem cell regulation. The fundamental importance of Notch to the healthy adult organism is illustrated by the impact Notch signal decline has on aging skeletal muscle repair13 and the important roles Notch has on the homeostasis of the intestine where Notch regulates the balance between proliferation and differentiation. Numerous associations have been found between loss and gain of function human Notch mutations and diseases including dementia, heart disease and cancer. We have found in Drosophila model organism that Notch can be activated by several different mechanisms both ligand-dependent or independent. These involve the activity of ubiquitin ligase regulators of Notch called Deltex and Su(dx) which target Notch to different trafficking pathways. Human homologues of these regulatory proteins are known but to date there is little information concerning how they function to regulate human Notch. This project will compare the regulation of Drosophila and human Notch through endocytic pathway regulation and identify whether different cancer-associated Notch mutations activate one pathway preferentially, thus laying the basis for future potential targeted therapeutic strategies for Notch-dependent cancers

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with experience in cell culture and signalling are encouraged to apply. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Drosophila ZO-1 protein Polychaetoid suppresses Deltex-regulated Notch activity to modulate germline stem cell niche formation. Open Biol. 7 pii: 160322.
Bonfini A, Wilkin MB, Baron M. (2015) Reversible regulation of stem cell niche size associated with dietary control of Notch signalling. BMC Dev Biol. 31;15:8.
Shimizu H, Woodcock SA, Wilkin MB, Trubenová B, Monk NA, Baron M. (2014) Compensatory flux changes within an endocytic trafficking network maintain thermal robustness of Notch signaling. Cell 157:1160-74.

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