Targeting Mitophagy: The Activity of Keap1 and its Cell-Protecting Reversible Inhibitors
Lead Supervisor: Geoff Wells (School of Pharmacy)
Co-Supervisor: Michelangelo Campanella (RVC, CfMR University College London)
Preservation of the quality of cell components is essential to cellular homeostasis. 'Autophagy' - the process by which specific malfunctioning organelles are self-digested is crucial to this cellular 'quality control'. In particular, autophagy targeted to mitochondria, known as 'mitophagy', is paramount to ensuring proper mitochondrial function. Such processes are important because defective mitochondrial quality control, mediated by mitophagy, is linked to some types of neurodenerative disease including Parkinson's Disease.
A number of natural products that interact with the protein Keap1 have broad cytoprotective activity including vascular and neuro-protective effects. These compounds have general effects on the cellular redox environment, in addition to specific activity relating to proteins involved in mitochondrial function.
Our aim is to develop a new series of Keap1 interactive small molecules that enhance the expression of antioxidant genes (inclduing redoxins and glutathione sythesis and conjugating enzymes) and increase sequestosome-I/p62 protein (a crucial arbiter of autophagy and mitophagy) activity.
The project will focus on the development of new compounds with potent and selective activity and the detailed biological evaluation of their effects on mitophagy and related processes (e.g. quantifying mitochondrial turnover, mapping p62/VDAC translocation/ubiquitylation, monitoring the Parkin-Pink1 pathways). The project will be multidisciplinary and span the interface between chemistry and biology.
Requirements
We seek a talented applicant with a background in chemical biology, pharmaceutical sciences or a related discipline. The practical training will span chemical synthesis through to detailed cell based pharmacological assays, and enable the student to develop a fundamental understanding of the science and techniques involved in drug discovery and translational biological research.
Key References
Narendra, D. et al. J. Cell Biol. 2008, 183, 795-803
Jin, S-M. et al. J Cell Biol. 2010, 191, 933-942.
Geisler, S. et al. Nat. Cell Biol. 2010, 12, 119-131.
Youle, R. & Narendra, D. Nat. Rev. Mol. Cell. Biol. 2011, 12, 9-14.
Hancock, R. et al. Free Radical Bio. Med. in press.
Seneviratne, M. et al. Int. J Immunopath. Ph. in press.
Further details about the project may be obtained from:
Lead Supervisor: Geoff Wells, geoff.wells@pharmacy.ac.uk, http://www.pharmacy.ac.uk/gwells.html
Co-Supervisor: Michelangelo Campanella, mcampanella@rvc.ac.uk, http://www.rvc.ac.uk/Staff/mcampanella.cfm
Further information about PhDs at the School of Pharmacy is available from:
Application forms and details about how to apply are available from:
Registry
The School of Pharmacy
University of London
19/39 Brunswick Square
London WC1N 1AX
United Kingdom
phd@pharmacy.ac.uk
+44 (0) 207 5831
http://www.pharmacy.ac.uk/apply_phd.html
Please submit the following supporting documents with your application form:
Transcripts: University examination transcripts and, if available, a copy of your degree certificate. Photocopies and/or certified translations accepted in the first instance.
English language: if your first language is not English, please provide evidence of English Language proficiency.
