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
IL-11 As A Novel Parietal Cell Cytokine That Blocks Gastric Acid Secretion And Causes Gastric Atrophy
Funder
National Health and Medical Research Council
Funding Amount
$524,820.00
Summary
Stomach cancer will kill a million people in the world in 2010, while in the western world the numbers of affectd indiviuduals are decreasing while in the in the developing world the opposite is the thus adding to the global health burden. Gastric atrophy is a pathological condition that always preceeds gastric cancer. This project aims to devlop our knowledge of the intitating events that allow atrophy to develop, thus informing us of novel ways of treating this condition before it bcomes cance ....Stomach cancer will kill a million people in the world in 2010, while in the western world the numbers of affectd indiviuduals are decreasing while in the in the developing world the opposite is the thus adding to the global health burden. Gastric atrophy is a pathological condition that always preceeds gastric cancer. This project aims to devlop our knowledge of the intitating events that allow atrophy to develop, thus informing us of novel ways of treating this condition before it bcomes cancerous.Read moreRead less
Transforming Growth Factor Beta As A Causal Factor In Human Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$634,359.00
Summary
Osteoarthritis (OA) is a common painful degenerative disease of the joints, which constitutes a major and growing public health problem, and for which there are no effective therapies. Our exciting recent research in the mouse has found that TGFb over-activity in the bone has a critical causal role in OA pathogenesis. Because TGFb silencing in bone could provide an entirely new way to slow the progression of OA, we propose to investigate this pathway in human OA.
Bacterial Mechanosensitive Channels As Novel Targets For Antibacterial Agents
Funder
National Health and Medical Research Council
Funding Amount
$424,500.00
Summary
The focus of this research is the development of new antibiotics to combat bacterial antibiotic resistance. Since their discovery antibiotics have had a profound effect on the health and well being of mankind, providing ready effective treatment for otherwise intractable infections. Although pencillin was initially effective against a large range of infections by the 1950s it was apparent that some bacterial strains had become resistant to this antibiotic. Partially in response to this resistanc ....The focus of this research is the development of new antibiotics to combat bacterial antibiotic resistance. Since their discovery antibiotics have had a profound effect on the health and well being of mankind, providing ready effective treatment for otherwise intractable infections. Although pencillin was initially effective against a large range of infections by the 1950s it was apparent that some bacterial strains had become resistant to this antibiotic. Partially in response to this resistance new antibiotics such as streptomycin, chloramphenicol and tetracycline were developed. These new drugs were potent against both Gram-positive and Gram-negative bacteria. However, there were early signs that resistance to these drugs was also emerging. For example, in 1953, during a Shigella outbreak in Japan, a strain of the dysentery bacillus was isolated which was multi-drug resistant, exhibiting resistance to chloramphenicol, tetracycline, streptomycin and the sulfanilamides. Multidrug-resistance in pathogenic strains of bacteria has in the last decade presented an increasing problem in treatment of bacterial infections and diseases. In 1994 a Melbourne public hospital reported a new antibiotic resistant strain of bacteria. This bacterium was resistant to vancomycin (the antibiotic used when all others have failed) and is known as VRE or vancomycin resistant enterococcus. Now strains of golden staph resistant to all antibiotics have appeared. The re-emergence of tuberculosis (TB), which kills more than 3 million people annually and which is spreading rapidly throughout the world, is also a serious threat, particularly as many strains are now multi-drug resistant. New antibiotics are needed that overcome bacterial drug resistance. It is anticipated that this research will lead to new antibiotics by exploiting molecular components of bacteria that have only recently been identified.Read moreRead less