Targeting cell death pathways in parasites
Project type
Honours and/or PhD
| Supervisor(s) | Division | |
| (Primary) | Structural Biology | .(JavaScript must be enabled to view this email address) |
Dr Erinna Lee (Co-supervisor) |
Structural Biology | .(JavaScript must be enabled to view this email address) |
Details of project
Recently the Fairlie laboratory discovered a cell death pathway in parasitic worms that cause schistosomiasis, one of the worlds major diseases. This pathway consists of about 10 different proteins and, whilst we have characterised a number of these biochemically, functionally and structurally, there are still others that require further investigation. This project will therefore initially be concerned with understanding what these proteins might potentially be doing in the worm, mostly through the use of biochemical and cell biology/tissue culture-based experiments.
In other studies we are working to establish the importance of this pathway in the whole organism. This aspect of the project will involve establishing strategies to introduce transgenes into the worms using viruses so as to interfere with aspects of their Bcl-2 pathway. The overall aim will be to determine whether components of this pathway could provide targets for the new drugs to treat schistosomiasis or, indeed, any parasitic infection where the infectious agent has a Bcl-2-regulated pathway.
Project references
- Lee EF, Clarke OB, Evangelista M, Feng Z, Speed TP, Tchoubrieva EB, Strasser A, Kalinna BH, Colman PM, Fairlie WD. Discovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes. Proc Natl Acad Sci USA. 2011 Apr 26;108(17):6999-7003. PMID: 21444803
- Hagen J, Lee EF, Fairlie WD, Kalinna BH. Functional genomics approaches in parasitic helminths. Parasite Immunol. 2011 Jun 29. doi: 10.1111/j.1365-3024.2011.01306.x. [Epub ahead of print] PMID: 21711361
Research interests
The Fairlie laboratory is interested in the molecular mechanisms underlying the fundamental cellular process of apoptosis, or programmed cell death. We use a combination of biochemical, cell biology and structural biology techniques to dissect the Bcl-2 mediated apoptosis pathways to better understand how cell death is regulated at a molecular level, and to create new tools that will help in the development of drugs.
More recently, my laboratory has become interested in the Bcl-2 pathway in the parasite that causes schistosomiasis, a major disease in developing countries. We will use similar approaches to dissect the apoptosis pathways in schistosomes with the aim of providing insights into whether these proteins will make good drug targets.
Selected publications
- Lee EF, Smith BJ, Horne WS, Mayer KN, Evangelista M, Colman PM, Gellman SH, Fairlie WD. Structural basis of Bcl-x(L) recognition by a BH3-mimetic α/β-peptide generated by sequence-based design. Chembiochem. 2011 doi: 10.1002/cbic.201100314. [Epub ahead of print] PMID: 21744457
- Lee EF, Fedorova A, Zobel K, Boyle MJ, Yang H, Perugini MA, Colman PM, Huang DCS, Deshayes K and Fairlie WD. Novel Bcl-2 homology (BH)-3 domain-like sequences identified from screening large peptide libaries for inhibitors of the pro-survival Bcl-2 proteins. J Biol Chem. 2011 284:31315-31326. PMID: 19748896
- Lee EF, Czabotar PE, Yang H, Sleebs BE, Lessene G, Colman PM, Smith BJ and Fairlie WD. Conformational changes in Bcl-2 pro-survival proteins determine their capacity to bind ligands. J Biol Chem. 2009 284:30508-30517. PMID: 19726685
- Lee EF, Sadowsky JD, Smith BJ, Czabotar PE, Peterson-Kaufman KJ, Colman PM, Gellman SH, and Fairlie WD. High-resolution structural characterization of a helical α/β-peptide foldamer bound to the anti-apoptotic protein Bcl-xL Angew Chemie Intl Ed .2009 48:4318-4322. PMID: 19229915
- Lee EF, Czabotar PE, van Delft MF, Michalak EM, Boyle M, Willis SN, Puthalakath H, Bouillet P, Colman PM, Huang DCS and Fairlie WD. A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation. J Cell Biol. 2008 180:341-355 PMID: 18209102
Research theme
Infectious diseases
Scientific discipline
- Biochemistry
- Cell Biology
- Molecular Biology
- Structural Biology
Keywords
apoptosis, Bcl-2, parasites, cell death