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
Assessment Of Development Of Resistance To Neuraminidase Inhibitors In A (H5N1) Influenza Viruses Using A Ferret Model
Funder
National Health and Medical Research Council
Funding Amount
$165,546.00
Summary
The neuraminidase (NA) inhibitors are considered the most effective anti-influenza drugs available for both prevention and treatment of influenza virus infection including A(H5N1) viruses. The drugs are effective against all subtypes of influenza A, making them ideal for use in the early months of a pandemic prior to an appropriate vaccine being produced. As a result many countries around the world, including Australia, have stockpiled these drugs (mainly Tamiflu) as part of their pandemic prepa ....The neuraminidase (NA) inhibitors are considered the most effective anti-influenza drugs available for both prevention and treatment of influenza virus infection including A(H5N1) viruses. The drugs are effective against all subtypes of influenza A, making them ideal for use in the early months of a pandemic prior to an appropriate vaccine being produced. As a result many countries around the world, including Australia, have stockpiled these drugs (mainly Tamiflu) as part of their pandemic preparedness plans. However, of concern is the increasing number of recent reports of a higher than expected level of resistance in epidemic influenza being generated against these drugs. A recent isolation of an H5N1 virus from a Vietnamese girl highlights that these viruses can also be resistant to Tamiflu. Within Australia, Tamiflu will be a critical weapon against the initial wave of an influenza pandemic, therefore it is vital that more is known about the propensity of the H5N1 virus to generate resistance, and possibly make these drugs clinically less effective. The aim of the project is to determine the levels, mode and type of resistance that may occur when ferrets are experimentally infected with HP A(H5N1) virus and then treated with NA inhibitors drugs such as Tamiflu. In the event of resistant viruses being isolated following drug pressure from Tamiflu, the strains will then be tested for their sensitivity to the other NA inhibitor drugs Relenza (zanamivir) or the peramivir (a third currently unlicensed NA inhibitor). The results from this cross resistance work will allow strategies to be put into place regarding the administration of an alternative NA inhibitor in the event of a pandemic virus acquiring particular NA mutations which may for example result in Tamiflu resistance. To determine the relative human risk of a NA inhibitor resistant A(H5N1) virus, studies to determine how infectious or transmissible the viruses are would be performed on all resistant strains isolated. NA inhibitor resistant strains demonstrate varying degrees of transmissibility and fitness, therefore it would be beneficial to classify this for any strains generated from this study so as to be in a better position to understand the public health implications if a particular resistant strain was to arise.Read moreRead less
Body Composition Changes In Cardiac Cachexia: Pathophysiology, Quantification And Approaches To Therapy
Funder
National Health and Medical Research Council
Funding Amount
$120,000.00
Summary
Cachexia is weight loss and weakness caused by disease, or as a side effect of illness. Congestive heart failure is a common cardiovascular condition that is accompanied by high mortality (up to 50% over 2 years) and considerable suffering. People with congestive heart failure often develop cachexia. This project will explore the mechanisms responsible for the development of cachexia using an animal model of cardiac cachexia that the researchers have developed. It will be complemented by an exam ....Cachexia is weight loss and weakness caused by disease, or as a side effect of illness. Congestive heart failure is a common cardiovascular condition that is accompanied by high mortality (up to 50% over 2 years) and considerable suffering. People with congestive heart failure often develop cachexia. This project will explore the mechanisms responsible for the development of cachexia using an animal model of cardiac cachexia that the researchers have developed. It will be complemented by an examination of the effects of exercise on measures of cachexia in patients with congestive heart failure. The researchers believe that this study will supply valuable new information about the development of cachexia and lead to new therapies for this syndrome.Read moreRead less