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Transforming Growth Factor Beta Signalling In Malignant Mesothelioma Growth And Collagen Production
Funder
National Health and Medical Research Council
Funding Amount
$509,917.00
Summary
Many cancers contain abundant connective tissue molecules called extracellular matrix (ECM) and data show that interaction of ECM with cells are important in the growth of cancers (1). Changes in expression of ECM and their receptors (integrins) have been associated with malignant changes in cells, enhanced tumour growth and resistance to chemotherapy (2,3). We have recently shown that inhibition of collagen, the most abundant ECM molecule produced by malignant mesothelioma (MM) cells, reduced M ....Many cancers contain abundant connective tissue molecules called extracellular matrix (ECM) and data show that interaction of ECM with cells are important in the growth of cancers (1). Changes in expression of ECM and their receptors (integrins) have been associated with malignant changes in cells, enhanced tumour growth and resistance to chemotherapy (2,3). We have recently shown that inhibition of collagen, the most abundant ECM molecule produced by malignant mesothelioma (MM) cells, reduced MM growth. How cancer cells regulate ECM production and control their growth is unclear but strong evidence suggests the growth factor transforming growth factor-beta (TGFB) plays an important role. We and others showed that MM cells secrete all forms (1-3) of TGFB, and TGFB1,2-like activity has been reported in pleural effusions from MM (4,5). All TGFB forms stimulate MM cells to grow and make ECM (6,7). We showed that high levels of collagen produced by MM are enhanced by TGFB. Small molecules called antisense oligonucleotides (AO) which blocked production of TGFB2 by cells, reduced MM cell growth in soft agar, a characteristic of cancer, and partially blocked MM growth in animal models (4,6). This was supported by studies using soluble TGFB type II receptors, which blocks TGFB1,3 (8), and our studies using TGFB2 specific antibodies, as both studies reduced tumour growth. These findings support a role for TGFB in MM growth. However, all TGFB forms can promote cell grow and collagen synthesis and therefore ways to block all TGFB forms are required to ensure maximal effect. This study will examine the effect of blocking common downstream signalling pathways of all three TGFB isoforms on MM collagen production and tumour growth. These pathways are activated when TGFB binds to its receptors sending messages to the nucleus of the cell to make collagen or grow. By identifying which TGFB signalling pathway is important, we may be able to design novel therapeutic approaches to help treat patients with this disease.Read moreRead less
Avian Influenza: Molecular Basis Of Potential Resistance To Neuraminidase Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$87,250.00
Summary
In this project we will visualize an avian flu protein bound to various antiviral drugs that are currently in the clinic (Relenza and Tamiflu) or are in clinical development. In the immediate term, the images derived from the project will be a valuable predictive tool for evaluating the likely effectiveness of antiviral drugs and vaccines in response to emerging viral resistance. In the longer term the images could be used to guide the development of new antivirals and vaccines against avian flu ....In this project we will visualize an avian flu protein bound to various antiviral drugs that are currently in the clinic (Relenza and Tamiflu) or are in clinical development. In the immediate term, the images derived from the project will be a valuable predictive tool for evaluating the likely effectiveness of antiviral drugs and vaccines in response to emerging viral resistance. In the longer term the images could be used to guide the development of new antivirals and vaccines against avian flu. This initiative brings together Industry leaders in the development of influenza antivirals and vaccines, CSL and Biota, with a leading Medical Research Institute.Read moreRead less
Genomic And Proteomic Profiling Of Dendritic Cell Heterogeneity
Funder
National Health and Medical Research Council
Funding Amount
$1,971,250.00
Summary
Dendritic cells (DC) present antigens to T cells and regulate immunity and tolerance. DC are heterogeneous, comprising seven functionally distinct subsets. We will use genomics and proteomics to identify the plasma membrane and endosomal proteins that underpin this functional heterogeneity. Such proteins are potential targets for improved protocols of vaccination and prevention of autoimmunity. This project will thus provide further opportunities for high-quality research and commercialisation.