Arthritis and Inflammation Research
ARTHRITIS AND INFLAMMATION RESEARCH CENTRE
The Arthritis and Inflammation Centre is headed by Professor John Hamilton who leads a team of scientists that focuses on inflammation-associated diseases, including arthritis, host pathogen interaction and cancer. The pathology of most diseases involve some degree of inflammation with macrophages often being the major cell type; as a result the Centre focuses primarily on macrophage biology and the effects of macrophage-associated inflammation on other cell types such as stem cells.
We employ a variety of techniques and strategies including gene-based strategies (for example, micro-array technology) to understand disease causation, protein-based strategies (including proteomics, immunoprecipitation, cell transfection) to study the cellular signal transduction pathways associated with disease, and mouse models and clinical material to analyse disease in vivo.
Key components of the biology involve an analysis of how macrophage lineage cells are altered during inflammatory disease, how at a molecular level these cells survive, proliferate, differentiate or are activated, and how to down-regulate the cellular functions aberrant in disease. There is some emphasis on growth factor biology/biochemistry and on signal transduction pathways implicated strongly in human arthritis, cancer and stem cell biology.
The role of urokinase plasminogen activator (u-PA) and its receptor (u-PAR) in arthritis and inflammation
Supervisor: A/Prof Andrew Cook and Dr Ming-Chin Lee
Project Site: Arthritis Research and Inflammation Centre, Department of Medicine (RMH), University of Melbourne
Contact: Dr Andrew Cook T: 8344 3290 E: adcook@unimelb.edu.au
Project Description: Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting approximately 1% of the population. Fibrin deposition, cell migration, and tissue destruction and remodeling are key components in the pathology of RA joints. The plasminogen activators (PAs), urokinase (u-PA) and tissue-type (t-PA), which converts plasminogen to plasmin, are implicated in these processes; however their precise roles in such processes, particularly for u-PA and its receptor (u-PAR), have yet to be defined. In this project you will study the role of u-PA and the u-PAR, in inflammation and arthritis using mice genetically altered mice such that u-PA or u-PAR have been rendered inactive. In particular, the effect of u-PA on cell migration to an inflammatory site, on tissue destruction and remodeling, and in activating/suppressing other key cytokines/proteases (eg metalloproteinases (MMPs)) involved in these processes will be studied.
Skill acquisition: experience with animal models of human disease, measurement of inflammatory mediator mRNAs by real time-PCR and their concentrations by ELISA, and the use of FACS and immunohistochemistry to study cell populations.
The role of granulocyte macrophage colony stimulating factor (GM-CSF) in arthritis and inflammation
Supervisor: A/Prof Andrew Cook and Dr Ming-Chin Lee
Project Site: Arthritis Research and Inflammation Centre, Department of Medicine (RMH) , University of Melbourne
Contact: Dr Andrew Cook T: 8344 3290 E: adcook@unimelb.edu.au
Project Description: Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting approximately 1% of the population. We have shown that GM-CSF is important for the development of several models of inflammation and arthritis. Furthermore, blockade of GM-CSF is effective at reducing arthritis severity. Phase 1 clinical trials are now underway in human rheumatoid arthritis. However, we still do not completely understand how GM-CSF is acting during inflammation and arthritis. In this project you will study the role of GM-CSF in inflammation and arthritis, and in particular, its role in monocyte/macrophage survival and activation.
Skill acquisition: experience with animal models of human disease, measurement of inflammatory mediator mRNAs by real time-PCR and their concentrations by ELISA, and the use of FACS and immunohistochemistry to study cell populations.
The role of a novel macrophage inflammatory mediator in arthritis
Supervisors: A/Prof Andrew Cook, Dr Ming-Chin Lee and Prof John Hamilton
Project Site: Arthritis Research and Inflammation Centre, Department of Medicine (RMH) , University of Melbourne
Contact: Dr Andrew Cook T: 8344 3290 E: adcook@unimelb.edu.au
Project Description: Through a microarray screen of inflammatory macrophages we have identified a novel potential therapeutic target for the treatment of arthritis. Macrophages are key cells involved in the destruction of joints during rheumatoid arthritis. In this project you will investigate the expression of this potential therapeutic target in patients’ tissue samples and in an inflammatory model of arthritis, and determine if targeting this protein would be a beneficial treatment. In this project you will be cutting tissue sections and measuring the expression of this novel protein. You will be inducing a murine model of arthritis and measuring a number of clinical parameters, collecting and processing tissue, and measuring gene/protein expression by histology, real-time PCR, Western blotting and FACS analysis. You will also be using siRNA, and nanoparticles to deliver therapeutic drugs in the arthritis model.
Skill acquisition: a variety of molecular and cell biological, and biochemical techniques, such as PCR and cloning of recombinant DNA; tissue culture, and FACS analysis, SDS-PAGE and Western blotting
Molecular signaling pathways controlling gene expression during chronic disease progression
Supervisors: Dr. Adrian Achuthan and Prof. John Hamilton
Project Site: Department of Medicine (RMH), University of Melbourne
Contact: Dr. Adrian Achuthan T: 8344 3298 E: aaa@unimelb.edu.au
Project description: Inflammation is now known to be associated with many chronic diseases such as cancer, Alzheimer’s disease, obesity/type II diabetes and heart disease. This project aims to understand molecular signalling pathways controlling the expression of genes critical for the progression of such diseases. In this project you will explore in molecular terms how a particular inflammatory cell type (macrophage/dendritic cell) can adapt to provide a pro-inflammatory environment with consequences for persistence or otherwise of these significant diseases. More specifically, you will investigate how transcription factors control the expression of pro-inflammatory and anti-inflammatory cytokines. Elucidation of these molecular pathways may lead to the development of novel therapies.
Techniques: You will acquire a wide-range of skills in cell biology (primary human monocytes/macrophage culture, ELISA assays, confocal microscopy and flow cytometry), and biochemistry and molecular biology (Western blotting, Real‐Time PCR and siRNA‐mediated gene knock-down).
Elucidating molecular signaling pathways controlled by anti-inflammatory steroids
Supervisors: Dr. Adrian Achuthan and Prof. John Hamilton
Project Site: Department of Medicine (RMH), University of Melbourne
Contact: Dr. Adrian Achuthan T: 8344 3298 E: aaa@unimelb.edu.au
Project description: Steroids (glucocorticoids) are widely used to treat the chronic inflammation and pain associated with many diseases such as rheumatoid arthritis and osteoarthritis. Unfortunately, there are side effects associated with usage of glucocorticoids in such diseases. In this project you will use genome-wide approaches such as microarray to indentify the genes that are regulated by glucocorticoids. More specifically, you will investigate molecular signalling pathways that lead to activation of transcription factors that lead to differential expression of glucocoritcoid-controlled genes in inflammatory conditions. Enhancing our understanding of molecular signalling pathways that are governed by glucocorticoids may lead to improved clinical therapies with minimal side effects.
Techniques: You will acquire a wide-range of skills in cell biology (primary human monocyte/macrophage culture, ELISA assays, confocal microscopy and flow cytometry), and biochemistry and molecular biology (Western blotting, Real‐Time PCR and siRNA‐mediated gene knock-down).