Understanding Sphingolipid Mediators Of Insulin Resistance
Funder
National Health and Medical Research Council
Funding Amount
$643,447.00
Summary
Sphingolipids are a class of lipid metabolites that have a variety of functions within cells. It has been known for some time that an accumulation of excess lipid, including certain sphingolipids, can adversely impact insulin action and glucose metabolism in cells. In this project we will a combination of strategies to test the hypothesis that the sphingolipid profile can be manipulated to have favourable effects on metabolism.
Development Of A New High Throughput Screen For Drug Binding To HERG K+ Channels
Funder
National Health and Medical Research Council
Funding Amount
$351,320.00
Summary
Inadvertent drug block of hERG, a potassium channel in the heart, can cause cardiac arrhythmias and sudden cardiac death. Screening for hERG toxicity has become a major hurdle for development of new drugs. We will use a mutant hERG protein that has enhanced drug binding to develop a high throughput test for hERG toxicity. Identification of dangerous drugs early in the drug discovery process will save the pharmaceutical industry millions of dollars in the costs of brining new drugs to market.
Centre Of Research Excellence In Medicines Intelligence
Funder
National Health and Medical Research Council
Funding Amount
$2,500,000.00
Summary
The NHMRC Centre of Research Excellence in Medicines Intelligence is a co-ordinated research program that will accelerate the development and translation of evidence on prescribed medicines use and outcomes for regulators and payers. The CRE is perfectly placed to embrace the national ‘call to action’ from the Health Minister's recent announcement to establish Quality Use of Medicine Safety as a National Health Priority.
Glycine Transporters regulate the concentration of glycine in the spinal cord and brain. It has been suggested that elevating glycine levels in these regions may be useful in treating pain and schizophrenia. This project will provide the basis for the development of new glycine transport inhibitors that may be used to treat these conditions.
Glucocorticoid Resistance In Paediatric Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$394,721.00
Summary
Glucocorticoids are among the most effective drugs used in the treatment of many haematological malignancies, including leukaemia, lymphoma and multiple myeloma. However, the development of tumour cell resistance to these drugs remains a significant problem, and clinically relevant mechanisms of glucocorticoid resistance remain poorly understood. This project aims to define mechanisms of resistance to glucocorticoids and develop new drugs to reverse resistance.
Translational Research Initiatives In Acute Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$631,010.00
Summary
Recent research has focussed on molecular characterisation of high-risk acute leukaemia subtypes. This proposal will combine the power of genomic analysis, global analysis of protein kinases and stringent preclinical drug testing in order to improve the treatment of these high-risk acute leukaemia subtypes. Several innovative and interrelated projects within this Program will utilise a unique and clinically relevant experimental model to achieve their goals.
Targeting Microtubules To Overcome Chemoresistance In Pancreatic Cancer
Funder
National Health and Medical Research Council
Funding Amount
$594,336.00
Summary
Pancreatic cancer is a devastating disease with a dismal prognosis because it is extremely resistant to chemotherapy agents. We plan to examine the expression of proteins called microtubules in pancreatic cancer and assess their role in drug resistance. It is anticipated that the findings of these studies will lead to the development of effective approaches to sensitise the cancer cells to chemotherapy agents.
Investigations of signals involved in redox-regulation of carbon storage. This project seeks molecular understanding of signals optimising storage processes in plants in response to nutrient supply and environmental stress. Discovering regulatory signals that control carbon storage and yield will maintain Australia's international reputation in this field of research and may provide technical opportunities to improve crops in healthy or stressful environments. This is an issue of increasing impo ....Investigations of signals involved in redox-regulation of carbon storage. This project seeks molecular understanding of signals optimising storage processes in plants in response to nutrient supply and environmental stress. Discovering regulatory signals that control carbon storage and yield will maintain Australia's international reputation in this field of research and may provide technical opportunities to improve crops in healthy or stressful environments. This is an issue of increasing importance especially in the context of global warming. Read moreRead less
Examination Of The Molecular Pharmacology Of Anthracyclines Induced Via Their Interaction With Iron
Funder
National Health and Medical Research Council
Funding Amount
$618,401.00
Summary
Anthracyclines are highly effective anti-cancer drugs, but their use is limited by toxic effects on the heart. This is thought to be due to these drugs directly binding iron (Fe). Indeed, we showed that anthracyclines induced marked changes in the way heart cells utilise Fe (DR1-3, 38; Mol. Pharmacol. 2002, 2003, 2004, 2005). We were the first to show that anthracyclines prevent Fe release from the criticial Fe storage protein ferritin. This prevents the use of Fe for vital processes eg. DNA and ....Anthracyclines are highly effective anti-cancer drugs, but their use is limited by toxic effects on the heart. This is thought to be due to these drugs directly binding iron (Fe). Indeed, we showed that anthracyclines induced marked changes in the way heart cells utilise Fe (DR1-3, 38; Mol. Pharmacol. 2002, 2003, 2004, 2005). We were the first to show that anthracyclines prevent Fe release from the criticial Fe storage protein ferritin. This prevents the use of Fe for vital processes eg. DNA and haem synthesis. Hence, this effect probably contributes to the cytotoxic activity of anthracyclines on the heart. We showed that novel drugs developed in my lab that bind Fe called chelators show high activity in animals (DR4) and prevent anthracycline-mediated Fe accumulation in ferritin. Importantly, Fe chelators have been shown to inhibit anthracycline-mediated cardiotoxicity. Indeed, the clinically used cardioprotective agent, ICRF-187, is actually an Fe chelator (5, DR6). However, ICRF-187 is not totally successful in terms of its cardioprotective effects and can cause myelosuppression (5, DR6). While the clinically used chelator, desferrioxamine (DFO), can prevent anthracycline-mediated cardiotoxicity, its poor membrane permeability limits its effectiveness. Our chelators are highly permeable and overcome the disadvantages of DFO (DR4). Thus, they are vital to examine for preventing anthracycline-mediated cardiotoxicity. In this proposal we will examine the changes in Fe metabolism induced by anthracyclines and test the hypothesis that novel Fe chelators may prevent the cardiotoxicity of these agents. We also aim to be the first to assess if preparation of anthracyclines which cannot bind iron prevents their cardiotoxicity. This will be done by preparing metal complexes of these drugs which prevent Fe-binding eg. anthracycline-zinc complexes. These studies are important for the development of less cardiotoxic forms of these very useful anti-tumour agents.Read moreRead less
Centre Of Research Excellence In Medicines And Ageing
Funder
National Health and Medical Research Council
Funding Amount
$2,601,415.00
Summary
Medicines have an important place in health and are commonly used for long periods, sometimes life-long. Using medicines wisely requires a careful balance between benefits and harmful effects. Currently, there is limited information to guide medicines use over a lifetime. Using large linked datasets, the CRE in Medicines and Ageing will generate much needed evidence about real world medicines use to support clinical and pharmaceutical policy decisions.