Biomarkers are biological substances, such as proteins, that can be used for diagnosis, measuring disease progression or the effects of treatment. Laura is examining levels of protein expression in laboratory models of MS and human brain tissue to help clarify unresolved issues in MS. In doing so, it is hoped that disease biomarkers originally identified in the laboratory model of MS will be applicable to people with MS. Biomarkers will play a vital role in future clinical practice as they may represent new targets for therapy or aid in earlier and more effective MS diagnosis.
MS is a key example of a complex disease that can benefit from the discovery of disease biomarkers, through the application of novel unbiased discovery tools such as proteomics – the investigation of all the proteins present in a particular biological situation. Currently there is a lack of biomarkers available to determine the early and accurate diagnosis of the disease, as well as a major inadequacy in terms of effective therapeutic interventions.
Biomarkers will also greatly help in clinical trials to test new therapeutic compounds by providing rapid tests to show whether the intervention is working or not.
It has recently come to light that the cerebellum and the brainstem of laboratory models of MS have increased susceptibility to blood brain barrier (BBB) disruption. However, to date there have been limited proteomic investigations of the molecular mechanisms leading to BBB breakdown and the associated neurological deficits.
This study will be the first of its kind applied to brain tissue involving state-of-the-art methods to obtain information about the type and quantities of proteins in both a laboratory model of MS and in human MS brain tissue. Clinical proteomics, the application of proteomics in the field of medicine, has the potential to revolutionise the field of clinical practice by providing a unique set of tools for defining disease states and improving individual tailoring of treatment.
The first stage of Laura’s project has been to look at the proteins that make up myelin in different regions of the brain and spinal cord in a healthy mouse. To do this she has been working with Prof Andrew Emili at his world-class proteomics laboratory at the Donnelly Centre for Cellular & Biomolecular Research at the University of Toronto (Canada). The quality of Laura’s work as part of her MS Research Australia Scholarship attracted further funding from the MS Society of Canada. This additional funding allowed Laura to work in Prof Emili’s lab and combine the expertise of the laboratories of Prof Emili and Associate Professor Purcell (Supervisor). This international laboratory experience can only enhance the quality of data Laura will obtain and help to form the international research connections that will enhance her future career.
Using the new technique available at Prof Emili’s laboratory, Laura identified over 1000 new proteins within the myelin. It is thought some of these proteins may play a role in myelin maintenance and repair, key processes that are impaired in MS.
Laura has now moved on to look at the protein composition of myelin in a laboratory model of MS. This phase of the project identified over 280 proteins which were present at different levels in the disease brains of mice with MS-like illness compared to healthy mice brains. When Laura examined blood cells, she saw almost 60 proteins with differing levels in the disease state.
In the final phase of her project, Laura returned to Associate Professor Purcell’s lab at the Monash University, and has undertaken additional work to validate the importance of these proteins in disease-affected regions of the brain in mice with MS-like illness. Using a number of different molecular techniques, Laura was able to systematically confirm that several key proteins are present at higher levels in diseased brain areas. These results provide unique insight into the disease origins and potential mechanisms for myelin damage occurring in MS.
Further research will investigate whether her recent findings can be translated to the disease course of people with MS. If successful, these proteins may provide help with earlier diagnosis of MS, monitoring of disease progression and the assessment of therapies.
Dagley LF, White CA, Liao Y, Shi W, Smyth GK, Orian JM, Emili A, Purcell AW. Quantitative proteomic profiling reveals novel region-specific markers in the adult mouse brain. Proteomics. 2013 (epub ahead of print)
Vuckovic, D.V., Dagley, L.F., Purcell, A.W. and Emili, A. Membrane proteomics by liquid-chromatography tandem mass spectrometry: Analytical approaches and challenges. Proteomics 13: 404-423
Dagley, L.F., Emili, A. and Purcell, A.W Application of quantitative proteomics technologies to the biomarker discovery pipeline for multiple sclerosis. Proteomics Clin Appl 7(1-2): 91-108
With two further manuscripts currently in preparation.
Updated: 04 January, 2009