Melanotransferrin: A “Missing Link” And A Novel Pharmacological Target For Treatment
Funder
National Health and Medical Research Council
Funding Amount
$613,848.00
Summary
Despite >30 years of research, the precise function of the protein, melanotransferrin (MTf), is unknown. However, we have breakthrough evidence that MTf stimulates WNT signalling as a major driver in cancer progression. We will investigate this hypothesis, which will underpin new cancer therapies. Indeed, we designed a new class of drugs that target the WNT pathway via up-regulating the WNT inhibitor, NDRG1. This drug (DpC) inhibits MTf expression to block tumour cell growth and metastasis.
Bias and allostery at the calcium sensing receptor. This project aims to provide a mechanistic and dynamic picture of the structure, function and physiology of the human calcium sensing receptor (CaSR), which is critical for vertebrate life. By responding to chemicals in the body, it acts as a universal nutrient sensor to maintain extracellular calcium homeostasis and mediate biological functions, including neurotransmission, inflammation, digestion, blood pressure and development. However, it i ....Bias and allostery at the calcium sensing receptor. This project aims to provide a mechanistic and dynamic picture of the structure, function and physiology of the human calcium sensing receptor (CaSR), which is critical for vertebrate life. By responding to chemicals in the body, it acts as a universal nutrient sensor to maintain extracellular calcium homeostasis and mediate biological functions, including neurotransmission, inflammation, digestion, blood pressure and development. However, it is not known how this single receptor controls the actions of multiple ligands to mediate numerous functions. By elucidating the roles of the CaSR and its ligands, this project aims to better understand fundamental physiological processes.Read moreRead less
Targeted development of dual action antitumour and antiangiogenic agents using differential and functional proteomics. There is an enormous need to develop more effective and less toxic therapeutic approaches to reduce the social and economic burden of cancer. The recent identification of small molecules that can act by both destroying cancer cells and the blood vessels that carry nutrients to them has provided a unique opportunity to define the pathways involved in the action of these agents in ....Targeted development of dual action antitumour and antiangiogenic agents using differential and functional proteomics. There is an enormous need to develop more effective and less toxic therapeutic approaches to reduce the social and economic burden of cancer. The recent identification of small molecules that can act by both destroying cancer cells and the blood vessels that carry nutrients to them has provided a unique opportunity to define the pathways involved in the action of these agents in order to develop more potent drug analogues. Development of these molecules will involve a collaborative and multidisciplinary link with our industry partner and the use of frontier technologies that may lead to improved health and economic outcomes for Australia. Read moreRead less
Regulation of large artery stiffness by endothelium-derived mediators and effects on the arterial pressure waveform. Stiffening of arteries is an important cardiovascular risk factor and increases with age, high blood pressure, high cholesterol and diabetes. Cells that line the blood vessels (endothelial cells), become damaged and this reduces the available amount of a dilator substance, nitric oxide, and increases the activity of a constrictor substance, endothelin-1. We have shown that nitric ....Regulation of large artery stiffness by endothelium-derived mediators and effects on the arterial pressure waveform. Stiffening of arteries is an important cardiovascular risk factor and increases with age, high blood pressure, high cholesterol and diabetes. Cells that line the blood vessels (endothelial cells), become damaged and this reduces the available amount of a dilator substance, nitric oxide, and increases the activity of a constrictor substance, endothelin-1. We have shown that nitric oxide regulates large artery stiffness and we believe that other endothelial mediators are also important regulators. Therefore, we aim to explore this in a series of studies. Regulation of stiffness of large arteries will improve treatment of age-related cardiovascular disease (eg isolated systolic hypertension)Read moreRead less
Oxytocin receptor PET ligands: imaging the love receptor’s engagement. This project aims to develop a positron emission tomography (PET) ligand for the oxytocin receptor. This novel platform is significant as it will allow the scientific community to answer questions about the role of the oxytocin receptor in the important process of social behaviour which underlies quality of life. This knowledge gap has remained unanswered for decades due to the lack of specific techniques to measure oxytocin ....Oxytocin receptor PET ligands: imaging the love receptor’s engagement. This project aims to develop a positron emission tomography (PET) ligand for the oxytocin receptor. This novel platform is significant as it will allow the scientific community to answer questions about the role of the oxytocin receptor in the important process of social behaviour which underlies quality of life. This knowledge gap has remained unanswered for decades due to the lack of specific techniques to measure oxytocin receptor engagement. It is also significant as it will equip Australian startup Kinoxis Therapeutics to progress their molecules to market, a process enabled by measuring oxytocin receptor engagement. Our dual expertise on the oxytocin receptor and PET ligand development uniquely situate us to generate this technology.Read moreRead less
Patient-centred EHealth Approach To Improving Outcomes For Gout Sufferers
Funder
National Health and Medical Research Council
Funding Amount
$688,354.00
Summary
Gout, caused by excessive urate, can be controlled by prescribing medication and patients adhering to them. We will conduct a 2-year controlled trial in primary care to test an eHealth tool to significantly improve gout patient outcomes. This tool tracks patients plasma urate, medication adherence, gout attacks and provides education, interaction with gout experts and reminders of medical visits. Nationwide rollout of this gout management tool will occur after improved outcomes are proven.
Development Of Iron Complexes For The Treatment Of FriedreichÍs Ataxia & The Role Of Frataxin In Iron Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$616,143.00
Summary
Friedreich's ataxia (FA) is a neuro- & cardio-degenerative disease where there is an accumulation of toxic iron (Fe) in the mitochondrion. Work from our current NHMRC grant showed iron plays a significant role in FA pathology In fact, the CIs dissected the mechanisms of mitochondrial iron-loading & have published 8 papers in high impact journals with 3 papers in PNAS USA in the last 2 yrs Understanding of this process has led to the design of rationalised drugs for FA This work in this Renewal c ....Friedreich's ataxia (FA) is a neuro- & cardio-degenerative disease where there is an accumulation of toxic iron (Fe) in the mitochondrion. Work from our current NHMRC grant showed iron plays a significant role in FA pathology In fact, the CIs dissected the mechanisms of mitochondrial iron-loading & have published 8 papers in high impact journals with 3 papers in PNAS USA in the last 2 yrs Understanding of this process has led to the design of rationalised drugs for FA This work in this Renewal could lead to novel therapies for FARead moreRead less
Pharmacological probes to facilitate preclinical development of modulators of a6 subunit containing nicotinic acetylcholine receptors. Allosteric modulators of alpha7 nicotinic acetylcholine receptors have a promising future as drugs targeting attention deficits in Alzheimer’s disease and schizophrenia but the mechanisms underlying modulation are poorly understood. This project aims to determine its binding site and develop a radioactive labelled compound that competes with its binding. The radi ....Pharmacological probes to facilitate preclinical development of modulators of a6 subunit containing nicotinic acetylcholine receptors. Allosteric modulators of alpha7 nicotinic acetylcholine receptors have a promising future as drugs targeting attention deficits in Alzheimer’s disease and schizophrenia but the mechanisms underlying modulation are poorly understood. This project aims to determine its binding site and develop a radioactive labelled compound that competes with its binding. The radiolabelled compound and a deeper insight into the mode of action will enable development of ligands for positron emission tomography (PET) which will aid in the development of BNC375 as well as other alpha7 modulators.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
Development Of Iron Chelators For The Treatment Of Friedreichs Ataxia And The Role Of Frataxin In Iron Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$550,987.00
Summary
Friedreich's ataxia (FA) is a neuro- and cardio-degenerative disease where there is an accumulation of toxic Fe in the mitochondrion. Excitingly, work from our current NHMRC grant showed iron plays a significant role in FA pathology. Importantly, we developed new drugs (Fe chelators) which rescue the cardiac pathology of FA in an animal model. Studies will now assess if our drugs prevent the neurodegeneration of FA in another animal model. This work could lead to novel therapies for FA.