Improving the function of GABA-A receptors is a key property of several classes of clinically important drugs including benzodiazepines and many anticonvulsants. However, the binding sites and molecular mechanisms of these drugs remain poorly understood. Using compounds similar to those in green tea, we will determine the molecular mechanism of these drugs. This understanding will lead to the development of better drugs for treatment of anxiety, depression, epilepsy, insomnia & schizophrenia.
Pharmacology Of Potential Anti-Tumour Agents: Iron And Copper Chelators Of The ApT, BpT And DpT Classes
Funder
National Health and Medical Research Council
Funding Amount
$647,137.00
Summary
Cancer cells take up more of the essential nutrients copper and iron than normal cells. Increased metabolism of these metals is linked to tumour growth progression. Our laboratory has developed compounds that bind these metals in tumours. Our studies suggest our novel compounds display a novel tumour targeting strategy which may explain their ability to also overcome drug resistance. This unique mechanism of action is crucial to understand for the development of novel anti-cancer agents.
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.
Resistance To Herceptin (trastuzumab) In HER2 Positive Breast Cancers: The Role Of Calcium Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$620,292.00
Summary
The monoclonal antibody therapy trastuzumab has revolutionized the treatment of women with Her2 positive breast cancer. Unfortunately some Her2 positive breast cancers do not respond to this therapy or gradually develop resistance. This project will define how an important cellular signal is remodeled in breast cancers resistant to trastuzumab. The ability of modulators of this signaling pathway to alter the sensitivity of breast cancers to trastuzumab will also be determined.
Transient Receptor Potential Calcium Channels In Breast Cancer Cell Proliferation, Apoptosis And Invasiveness
Funder
National Health and Medical Research Council
Funding Amount
$104,018.00
Summary
Calcium is a highly regulated signal used by cells to control processes such as growth and division, cell death and motility. Calcium channels let calcium into the cells, and specific calcium channel types are overexpressed in cancers, including those of the prostate and breast. In this research, we will assess the role of specific calcium permeable channels known as TRPs in breast cancer and the consequences of their inhibition on breast cancer cell growth and survival.
Characterization Of The Novel Drug And Xenobiotic Metabolizing UGT3A Enzyme Family
Funder
National Health and Medical Research Council
Funding Amount
$578,352.00
Summary
The elimination of chemicals made in the body or from environmental sources is essential for the maintenance of good health and the prevention of debilitating diseases. We have discovered two enzymes that use glucose and other sugars to detoxify fat-soluble chemicals. In this project we will study how these enzymes work and how they are regulated in the body. With this knowledge, we may be able to target the processes of drug and chemical detoxification to make them more efficient.
Finely Tuned Glutamate Receptor Inhibitors As Novel Therapeutics For Neurodegenerative Disorders
Funder
National Health and Medical Research Council
Funding Amount
$1,168,829.00
Summary
Neurodegenerative disorders are among the leading causes of death and disease burden. New drugs are needed to treat both symptoms and disease progression. This project aims to understand the properties of different drug-like compounds to inhibit proteins on the surface of brain cells (glutamate receptors) to impact disease progression and symptoms in a preclinical disease models. The project will yield a better understanding of how best to target glutamate receptors for therapeutic effect.
Elucidation Of The Molecular Requirements Of The Low Affinity 'state' Of The Beta1-adrenoceptor
Funder
National Health and Medical Research Council
Funding Amount
$535,500.00
Summary
Beta-blockers are used for the management of cardiovascular diseases including heart failure, ischaemic heart disease and high blood pressure. Beta-blockers mostly work by blocking the effects of a naturally occuring chemical called noradrenaline. Beta-blockers can be used to prevent noradrenaline induced increases in the rate and force of human heart contraction. We have discovered that one group of beta-blockers exemplified by CGP 12177 has the remarkable property of not only being able to blo ....Beta-blockers are used for the management of cardiovascular diseases including heart failure, ischaemic heart disease and high blood pressure. Beta-blockers mostly work by blocking the effects of a naturally occuring chemical called noradrenaline. Beta-blockers can be used to prevent noradrenaline induced increases in the rate and force of human heart contraction. We have discovered that one group of beta-blockers exemplified by CGP 12177 has the remarkable property of not only being able to block beta-receptors but they can also stimulate them at higher concentrations. Thus low concentrations block the effects of noradrenaline, but higher concentrations stimulate the receptor. More puzzling is that the stimulant effects of this group of beta-blockers cannot be easily blocked. To explain this we hypothesize that human beta-receptors can exist in two different 'states'. One 'state' can be stimulated by noradrenaline and blocked by low concentrations of beta-blockers such as propranolol and CGP 12177. Another 'state' of the same receptor is resistant to blockade by beta-blockers such as propranolol but can be stimulated by beta-blockers such as CGP 12177. This project seeks to investigate the molecular basis of the beta-adrenoceptor that is responsible for stimulant effects of beta-blockers. Specifically it explores the components of the beta-adrenoceptor that are critically and uniquely important for interacting with the stimulant beta-blockers. This project is an important increment in our laboratories research program to increase our understanding of the effects of beta-blockers. Our long term goal is to be able to develop beta-blockers that can block both states of the beta-adrenoceptor to provide a more effective block of the receptor and in particular for the improved management of heart failure.Read moreRead less
Molecular Determinants Of UDP Glucuronosyltransferase 1A3 And 1A4 Expression
Funder
National Health and Medical Research Council
Funding Amount
$516,078.00
Summary
Enzymes in the liver and gastrointestinal tract have a crucial role in protecting against the toxic effects of fat-soluble chemicals. Two of these enzymes called UGT1A3 and UGT1A4 have a special role in protecting against drugs and toxins that contain nitrogen groups. The levels of these two enzymes in the liver and gut vary extensively between individuals. In this project we will determine how the levels of these enzymes are controlled and what is the cause of this variability between individua ....Enzymes in the liver and gastrointestinal tract have a crucial role in protecting against the toxic effects of fat-soluble chemicals. Two of these enzymes called UGT1A3 and UGT1A4 have a special role in protecting against drugs and toxins that contain nitrogen groups. The levels of these two enzymes in the liver and gut vary extensively between individuals. In this project we will determine how the levels of these enzymes are controlled and what is the cause of this variability between individuals. This will help us predict those individuals who are more at risk from the adverse effects of nitrogen-containing drugs and from the toxic effects of chemicals in the diet or the environment. This project will also help us develop methods to increase the levels of these protective enzymes and help reduce the effects of exposure to toxic chemicals.Read moreRead less
Probing UDP-glucuronosyltransferase Protein-protein Interactions: The Power Of Two.
Funder
National Health and Medical Research Council
Funding Amount
$482,710.00
Summary
Drugs and other chemicals (eg. dietary constituents, environmental pollutants, and chemicals that occur naturally in the body - such as steroid hormones) are broken down by specialised proteins called enzymes. This process is referred to as biotransformation, or 'metabolism'. Drug and chemical metabolism serves as a detoxification mechanism (since the products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. UDP-Glucuronosyltransfera ....Drugs and other chemicals (eg. dietary constituents, environmental pollutants, and chemicals that occur naturally in the body - such as steroid hormones) are broken down by specialised proteins called enzymes. This process is referred to as biotransformation, or 'metabolism'. Drug and chemical metabolism serves as a detoxification mechanism (since the products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. UDP-Glucuronosyltransferase (UGT) is one of the most important enzymes involved in drug and chemical metabolism. Consistent with its ability to metabolise such a large number of compounds, UGT is known to exist as a 'superfamily' of structurally related proteins. Despite the importance of UGT, little is known about the structural characteristics of these enzymes that are responsible for recognising and binding different classes of chemicals. Accumulating evidence from this and other laboratories indicates that the individual UGT proteins may combine with themselves (to form a homodimer) and with other UGT proteins (to form heterodimers). This project largely seeks to define the scope of UGT homo- and hetero- dimerisation, identify the structural elements of the proteins responsible for association and characterise the functional significance of dimerisation. The project will further explore associations between UGTs and other proteins, namely albumin. Characterisation of UGT dimerisation and associations with other proteins is fundamental to our understanding of how this enzyme functions and selects particular chemicals for metabolism. The work also has important implications for the devlopment and interpretation of in vitro (or 'test-tube') approaches for predicting how drugs are metabolised in humans. Such tests are widely employed in research and pharmaceutical company laboratories to predict how the body 'handles' new drugs prior to their administration to humans.Read moreRead less