Molecular Immunopathology Unit - Honours projects available in 2010
An Honours project undertaken in this lab would be administered by the Discipline of Pathology.
Focuses on understanding how infectious diseases affect the brain, sometimes fatally, and on the roles of the kynurenine pathway in health and disease
- Recent interesting publications
- Hunt NH, Grau GE. Cytokines: Accelerators and brakes in the pathogenesis of cerebral malaria. Trends in Immunology 2003;24:491-499.
- Ball HJ, Sanchez-Perez A, Weiser S, Austin CJ, Astelbauer F, Miu J, McQuillan JA, Stocker R, Jermiin LS, Hunt NH. Characterization of an indoleamine 2,3-like protein in humans and mice. Gene 2007:396:203-213.
- Miu J, Mitchell AJ, Muller M, Carter SL, Ball HJ, Saunders B, Lu B, Campbell IL, Hunt NH. Chemokine expression during fatal murine cerebral malaria and protection associated with CXCR3 deficiency. Journal of Immunology 2008:180:1217-1230.
- Understanding a key new enzyme in the kynurenine pathway
Supervisor + contact details:
- Dr Helen Ball
- Professor Nicholas Hunt
Tryptophan is an essential amino acid. The enzyme indoleamine dioxygenase (IDO) catalyses the conversion of tryptophan into kynurenine, which is then transformed into several biologically active molecules. This pathway is involved in several very important physiological and pathophysiological processes, including immunomodulation and central nervous system disorders. We recently discovered a second enzyme (IDO2) that facilitates the same reaction as IDO (now termed IDO1), but which is found in different anatomical locations.
This project will further investigate where IDO2 is expressed, by looking at subcellular localisation and tissue expression during development and disease states. The phenotypic characteristics of a newly-developed IDO2 gene knockout mouse, e.g. susceptibility to infectious disease (malaria and meningitis), also will be investigated.
Laboratory techniques: immunohistochemistry, immunofluorescence microscopy, quantitative RT-PCR, cell culture, transfection, biochemical assays, mouse models of disease. Day-to-day laboratory supervision and instruction in techniques will be given by senior researcher Dr Helen Ball.
- What causes death and disability in bacterial meningitis?
Supervisor + contact details:
- Professor Nicholas Hunt
- Dr Helen Ball
- Dr Andrew John Mitchell
Bacterial meningitis kills over 150,000 people every year and many more suffer neurological consequences that persist after the infection is eliminated. It is important to study the pathogenesis of this disease in order to discover new ways of reducing both the death toll and the incidence of the long-term problems in survivors. We are applying our extensive experience in uncovering the immunopathological mechanisms in cerebral malaria to the problem of bacterial meningitis. We have established a mouse model of bacterial meningitis and our preliminary results suggest that certain cytokines play an important role in determining whether mice with bacterial meningitis succumb to the disease. These cytokines also may be important in the development of behavioural defects in survivors. The kynurenine pathway also seems to be relevant in this condition. Activation of this pathway is observed in a number of other central nervous system disorders, including cerebral malaria.
This project will further investigate the role of cytokines and inflammatory processes in bacterial meningitis. We already have performed microarray analysis to determine the global gene expression pattern during the course of meningitis. The expression of individual genes will be verified at the mRNA or protein levels and correlated with the appearance of histopathological and behavioural changes in these mice. In this way we will identify new pathways in the host response to bacterial infection of the brain.
Laboratory techniques: mouse models of disease, mouse behavioural studies, quantitative RT-PCR, histopathology, biochemical assays, immunohistochemistry. Day-to-day lab supervision and instruction in techniques will be given by senior researchers Drs Mitchell and Ball.
For all projects, MIU scholarships will be available for candidates with high WAMs.
- How does an anti-inflammatory steroid reduce the lung oedema caused by malaria?
Supervisor + contact details:
- Professor Nicholas Hunt
- Dr Andrew John Mitchell
- Dr Helen Ball
Oedema (the build up of extracellular fluid) in the lung is a common and deadly complication of malaria infection. We have devised and characterized a new mouse model of lung oedema caused by malaria. Leukocytes enter the lung tissue from the blood and fluid builds up in the interstitial and alveolar spaces. Among many interventions that we have tested, treatment with the anti-inflammatory agent dexamethasone is by far the best at preventing this oedema.
We now need to establish the mechanism through which dexamethasone is acting in this disease model. First we will use microarray technology to compare global gene expression in normal and malaria-infected mice, with or without dexamethasone treatment. Then we will study the infiltration of leukocytes into the lung tissue. Correlations will be made between gene expression, leukocyte infiltration and the occurrence of lung oedema. This will allow us to identify some key pathophysiological mechanisms that lead to pulmonary oedema in malaria infection, and possibly reveal new routes to effective prevention or treatment of disease.
Laboratory techniques: gene expression by microarray or RT-PCR, flow cytometry, mouse model of disease, microscopy, histopathology. Day-to-day laboratory supervision and instruction in techniques will be given by senior researchers Drs Mitchell and Ball.
