Tilley Laboratory
Department of Biochemistry
Research -
Malaria and Human Red Blood Cells
Work in Prof Tilley's laboratory aims to use molecular and cell biological approaches to understand the interactions of the malaria parasite with the erythrocytes of its human host. It is hoped that these studies will lead to the development of new antimalarial strategies.
The major areas of the research are:
Studies of protein trafficking and cellular architecture in malaria parasite-infected erythrocytes
The malaria parasite spends part of its life-cycle inside the erythrocytes of its human host where it modifies the erythrocyte membrane to promote its own growth and survival. To do this the intracellular parasite has to export proteins outside the boundaries of its own plasma membrane.
The molecular machinery and the mechanisms of transport involved in this external transport system are not yet understood and the signals that direct trafficking appear to be different from those used in mammalian systems. Characterization of the components of the secretory pathway in the malaria parasite may lead to the development of novel antimalarial strategies. Paul McMillan is a La Trobe University Research Fellow and Matt Dixon an NHMRC-funded Research Fellow working on molecular aspects of this project. Dr Alex Maier, an independent investigator at La Trobe University, is also collaborating in this project. Eric Hanssen has developed electron tomography methods to image the secretory network at very high resolution.
Prof Tilley's laboratory uses cell biology and transfection techniques to identify the parasite components responsible for these unusual trafficking events and to dissect the sequences within exported polypeptides that are required for correct trafficking. A bioinformatics tool (MalSig) has been generated to predict the unusual recessed signals of some exported parasite proteins.
Prof Tilley and colleagues have set up a confocal microscope facility and developed techniques for fluorescence photobleaching and fluorescence correlation spectroscopy of green fluorescent protein in transfected parasites to study locations and dynamics of parasite proteins in live cells. This work is performed in collaboration with Dr Nick Klonis (La Trobe University), and with Professor Alan Cowman, Walter and Eliza Hall Institute.
Professor Tilley is Deputy Director of a new ARC Centre of Excellence for Coherent X-ray Science (www.coecxs.org) sharing a $15 million grant from the Australian Research Council, Victorian Government and University sector. The Centre brings physicists, chemists and biologists together to develop fundamentally new approaches to probing biological structures and processes. It combines world-class expertise in imaging, structural biology, laser science and molecular theory. The project is developing novel high-resolution imaging using the Australian Synchrotron, and ultimately x-ray lasers, to determine the structures of important drugs targets whose molecular architecture cannot be determined with current techniques. Prof Tilley's laboratory is using novel coherent X-ray diffraction imaging technique to image the ultrastructure of malaria parasite-infected erythrocyte.
This work is performed in collaboration with Assoc Prof Mike Ryan and Associate Professor Andrew Peele (La Trobe University).
Vacation scholarships and Postgraduate scholarships to work with members of the Centre for Excellence for Coherent X-ray Science are available.
Development of novel antimalarial drugs
The malaria parasite is rapidly developing resistance to all of the antimalarial drugs currently available. As the malaria parasite is already responsible for an estimated 2 million deaths per annum, it is essential that new drugs be synthesised or that therapies be developed to overcome drug resistance. To do this it is important to understand the molecular basis of drug action and drug resistance.
Many antimalarial drugs, such as chloroquine and artemisinin, are thought to interfere with or to be activated by the digestion of hemoglobin in the blood stages of the malaria life cycle. The parasite degrades hemoglobin to amino acids in an acidic food vacuole, producing free haem and reactive oxygen species as toxic by-products. Chloroquine and artemisinin are thought to target the parasite’s waste disposal system however the exact mechanisms of killing are not understood. Prof Tilley's laboratory is currently undertaking a study of the toxic effects of these drugs on the parasite to try to pin-point the killing mechanisms and to understand mechanisms of resistance. This information is used in the design of novel quinoline and endoperoxide antimalarial drugs. This work is performed in collaboration with Dr Nick Klonis.
Clickherefor a link to information about Leann Tilley available through the Australian Research Council (ARC) and the National Health and Medical Research Council (NHMRC) Research Network for Parasitology
Please click here for a biosketch of Leann Tilley.
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