Towards Reducing Resistance And Haematological Toxicity Of Linezolid
Funder
National Health and Medical Research Council
Funding Amount
$135,825.00
Summary
Multi-drug resistance in bacteria is increasing at an alarming rate. We have diminishing therapeutic options, and there are few antibiotics in the drug development pipeline that offer much hope. It is therefore important that we look towards ways of further optimising the use of antibiotics that we currently have available. An important last line of defense drug, linezolid, has been available in Australia for less than 2 years and already resistance is occuring. In addition, with broader use of ....Multi-drug resistance in bacteria is increasing at an alarming rate. We have diminishing therapeutic options, and there are few antibiotics in the drug development pipeline that offer much hope. It is therefore important that we look towards ways of further optimising the use of antibiotics that we currently have available. An important last line of defense drug, linezolid, has been available in Australia for less than 2 years and already resistance is occuring. In addition, with broader use of this drug outside clinical trials, there has been an increasing concern over its toxicity to important blood cells. We seek to better understand the determinants of linezolid resistance and toxicity, so that novel dosing strategies may be developed to optimise its use (reduce toxicity and enhance efficacy) thereby extending the usefulness of this last line of defense antibiotic.Read moreRead less
Overcoming Breast Cancer Heterogeneity And Resistance Using A Novel Therapeutic Approach Targeting The Metastasis Suppressor NDRG1.
Funder
National Health and Medical Research Council
Funding Amount
$431,000.00
Summary
Breast cancer (BrCa) is the leading cause of cancer death in women and current treatments suffer from development of resistance, leading to metastatic progression. I will assess a novel treatment strategy for BrCa, targeting a gene that is able to inhibit multiple key drivers of BrCa, using a novel potent and selective anti-cancer agent. This approach has the potential to overcome resistance to current therapies and alleviate the onset of metastasis, to improve prognosis for BrCa patients.
TACI: A Novel Immune Checkpoint In Chronic Lymphocytic Leukemia
Funder
National Health and Medical Research Council
Funding Amount
$874,462.00
Summary
Chronic Lymphocytic Leukemia (CLL) is a very common blood cancer. CLL cells actively shut down immune defenses in patients. Moreover, current as well as emerging more targeted therapies suppress immunity and over a quarter of patients will die from an infection despite a good response to cancer treatments. Our laboratory has gained new understanding in the mechanism of action of a new treatment for CLL called Ibrutinib. This information allows us to design improved treatment options for CLL.
Relaxin Receptor Structural Determination To Aid Therapeutic Development
Funder
National Health and Medical Research Council
Funding Amount
$1,249,114.00
Summary
The receptor for the peptide hormone relaxin, RXFP1, is being targeted by numerous drug companies for the treatment of cardiovascular disease. However, the lack of molecular detail of how relaxin binds and activates RXFP1 is hindering new drug development. We will determine the structure of the complex of relaxin bound to RXFP1 and the mechanism by which this activates cells. The knowledge gained will aid in the design of new drugs targeting RXFP1 for the treatment of cardiovascular disease.
Epigenetic Therapies As Molecular Probes To Investigate The Molecular Pathogenesis Of Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$937,402.00
Summary
A major limitation to the success of targeted therapies in cancer is the fact that we have few if any tools to study in detail their mechanism of action within cancerous and normal cells. If we were able to visualise these drugs within cells and precisely characterise the proteins, DNA and RNA within a cell that interact with these therapies we will be able to identify strategies that can optimise their efficacy and reduce the side-effects of these treatments.
Functional Modulation Of Ovine And Human Somatotropes By In Vitro Application Of Leptin
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Obesity is a common disorder in developed countries and a prevalent condition which is often stigmatized. Actuarial data indicate that life expectancy is reduced when body-mass index (body mass in kg-square of the height in metres) is 20% or more above the ideal (obesity is >28% above ideal). Growth hormone (GH) from pituitary gland is the major anabolic hormone to increase muscle and reduce fat. A significant reduction in GH is found in obesity. Indeed, visceral fat mass is primary negative ....Obesity is a common disorder in developed countries and a prevalent condition which is often stigmatized. Actuarial data indicate that life expectancy is reduced when body-mass index (body mass in kg-square of the height in metres) is 20% or more above the ideal (obesity is >28% above ideal). Growth hormone (GH) from pituitary gland is the major anabolic hormone to increase muscle and reduce fat. A significant reduction in GH is found in obesity. Indeed, visceral fat mass is primary negative statistical determinant of GH secretion in middle age men and women. It is clear that the reduction in GH is due to a low sensitivity of GH cells to GH-releasing hormone (GHRH) from brain. It is therefore necessary to understand the change of pituitary GH cells in obesity. A recently identified, fat cell secreted, polypeptide (leptin) is demonstrated to reduce food intake and increase energy expenditure. Receptors for leptin have been found in pituitary gland, mainly in GH secreting cells. In our preliminary experiments, leptin reduces GH secretion by decreasing GHRH receptor synthesis. Meanwhile, this leptin treatment increased the receptors for GH-releasing peptide (GHRP), a synthetic peptide stimulating GH secretion. We aim to investigate the effect of leptin on cultured ovine and human GH cells by studying important cell functions including hormone and receptors synthesis, intracellular signaling molecules, membrane ion channels and cellular secreting machinery. The results will clarify the mechanism underlying GH deficiency in obese patients. We will also test the effect of synthetic GHRP in combination with leptin in vitro. The relationship between GHRP and leptin on the functional modification of GH cells will also be studied. It is likely to see that GHRP reduces the inhibitory effect of leptin on GH cells. This may end up an effective therapeutical use of GHRP (oral available) in the treatment of obesity.Read moreRead less
Novel Targeted PEG Nanoparticles For Cancer Treatment And Monitoring
Funder
National Health and Medical Research Council
Funding Amount
$606,979.00
Summary
We will develop novel targeted cancer therapies based on next generation nanoparticles. These particles will deliver highly potent drugs to tumours with less adverse effects to healthy organs. The ability to image the therapeutic can be used to detect diseases at early, potentially curable stages, identify patients likely to respond to certain treatments, and predict response to therapy. Our project has the potential to increase the survival of patients suffering from the most deadly cancer.
A National Resource For Mouse Models Of Mesothelioma
Funder
National Health and Medical Research Council
Funding Amount
$483,643.00
Summary
Mouse models of mesothelioma have led to a greater understanding of the disease and the identification of potential drug therapies some of these have now been translated into clinical trials. In the existing models, mesothelioma cells that have been grown in the laboratory are transplanted into animals by injecting the cells under the skin. Different cell lines with different properties are used in different experimental protocols. This application will fund the establishment of a central resour ....Mouse models of mesothelioma have led to a greater understanding of the disease and the identification of potential drug therapies some of these have now been translated into clinical trials. In the existing models, mesothelioma cells that have been grown in the laboratory are transplanted into animals by injecting the cells under the skin. Different cell lines with different properties are used in different experimental protocols. This application will fund the establishment of a central resource to maintain and distribute these cell lines. In addition, we describe a new transgenic mouse model in which mesotheliomas are rapidly induced in the peritoneal cavity after exposure to asbestos, recreating the natural tumour development much more accurately. These mice have been engineered to express the cancer causing protein of a monkey virus (SV40 large T antigen) in their mesothelial cells because it has been suggested that the virus has a role in the development of mesothelioma. This application also seeks funding to use the MexTAg mice to test the usefulness of different therapies for the prevention or treatment of mesothelioma. These animals give us the ability to investigate the disease in a more realistic environment than previous models. In parallel collaborative studies with other groups investigating different aspects of the biology of this cancer, we plan to analyze the earliest changes in the development of the disease and search for early markers using proteomics and gene expression studies. We anticipate that this model will generate information more directly relevant to understanding the human disease and will provide essential experimental data for clinical trials.Read moreRead less