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
Novel G-protein Coupled Receptors LGR7 And LGR8; The Receptors For Relaxin And Insulin-like Peptide 3 (INSL3)
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Relaxin is a hormone which has long been known to have essential roles in pregnancy and birth. However it has also been demonstrated to have far broader involvement in the functioning of the kidney, heart and central nervous system. Furthermore, mice lacking relaxin show increased collagen, or fibrosis, in their internal organs and skin as they age. This progressive fibrosis leads to problems with bodily functions. Treatment of these mice with relaxin reverses the fibrosis and restores function, ....Relaxin is a hormone which has long been known to have essential roles in pregnancy and birth. However it has also been demonstrated to have far broader involvement in the functioning of the kidney, heart and central nervous system. Furthermore, mice lacking relaxin show increased collagen, or fibrosis, in their internal organs and skin as they age. This progressive fibrosis leads to problems with bodily functions. Treatment of these mice with relaxin reverses the fibrosis and restores function, hence relaxin has great potential as a treatment for fibrotic diseases. Anti-fibrotic drugs are a major target for drug companies as suitable compounds are not currently available. Research into the mechanisms whereby relaxin exerts its cellular effects has been limited by the inability of researchers to identify its receptor. We now know that relaxin acts through a novel G-protein coupled receptor (GPCR) LGR7 and will also act on a related receptor LGR8. The LGR8 receptor is actually the receptor for a hormone with similarities to relaxin, INSL3. It is essential that an appreciation of relaxin receptor function is obtained not only for its important actions in pregnancy, but also for its clinical applications. In this regard, improved understanding of how relaxin interacts with these two receptors is essential. We will use our expertise in producing these hormones together with molecular techniques to produce the receptor, to study the interaction of relaxin and INSL3 with these receptors and the subsequent cellular events that occur. Furthermore, to more effectively use relaxin as a drug, we need to discover a smaller, more potent and orally active form of the hormone. We will develop novel technologies to aid in the discovery of the next generation of relaxin drugs. This multi-disciplinary approach will allow us to fully maximise the clinical potential of this enigmatic hormone.Read moreRead less
Design And Use Of Human Hematopoietic Prostaglandin D2 Synthase Inhibitors In Allergic Asthma And Bone Diseases
Funder
National Health and Medical Research Council
Funding Amount
$517,960.00
Summary
Many currently used non-steroidal anti-inflammatory drugs are burdened by side effects such as gastrointestinal bleeding or increased risk of heart attack. This is because they ablate the production of a class of molecules called prostaglandins. We believe it is possible to fine tune the action of these drugs and reduce the side effect risk. There is evidence to suggest that only some prostaglandins are involved in inflammation, so the risk of side effect can be reduced by blocking the productio ....Many currently used non-steroidal anti-inflammatory drugs are burdened by side effects such as gastrointestinal bleeding or increased risk of heart attack. This is because they ablate the production of a class of molecules called prostaglandins. We believe it is possible to fine tune the action of these drugs and reduce the side effect risk. There is evidence to suggest that only some prostaglandins are involved in inflammation, so the risk of side effect can be reduced by blocking the production of only a small set. One prostaglandin, prostaglandin D2, is known to cause many characteristics of allergic asthma and may also contribute to osteoarthritis, although the evidence for this is contradictory. We will determine any therapeutic benefit to blocking the production of prostaglandin D2 in these diseases by developing compounds that only inhibit the enzyme responsible for its production.Read moreRead less
Evaluation Of Factor Va From The Venom Of The Australian Brown Snake As A Topical And Systemic Anti-bleeding Agent
Funder
National Health and Medical Research Council
Funding Amount
$113,742.00
Summary
Anti-bleeding agents are important pharmaceuticals for use in truama, surgery and several medical conditions to reduce blood loss and the need for blood transfusion. Some Australian snakes contain in their venom a powerful blood clotting agent. This agent mimics the human clotting machinery. In this project, we plan to test purified components of snake venom for an ability to clot human blood. We will undertake laboratory test-tube experiments as well as using an animal model after ethical appro ....Anti-bleeding agents are important pharmaceuticals for use in truama, surgery and several medical conditions to reduce blood loss and the need for blood transfusion. Some Australian snakes contain in their venom a powerful blood clotting agent. This agent mimics the human clotting machinery. In this project, we plan to test purified components of snake venom for an ability to clot human blood. We will undertake laboratory test-tube experiments as well as using an animal model after ethical approval. This project seeks to capture some of the genetic blueprint of an Australian snake, for human benefit by developing a new therapeutic agent based on a venom component. If the experiments are successful, the next stage will be further testing of efficacy and toxicity before seeking approval for clinical trials. The research is supported by the Australian pharmaceutical company QRx Pharma Pty Ltd who will work with Uniquest Pty Ltd to protect intellectual property generated in the project.Read moreRead less
MITOCHONDRIA, OXIDATIVE STRESS AND NEURONAL APOPTOSIS: BIOCHEMICAL, CELLULAR AND PHARMACOLOGICAL APPROACHES
Funder
National Health and Medical Research Council
Funding Amount
$145,880.00
Summary
Our goal is to understand the detailed process whereby nerve cells die after various stresses and injury. We aim also to develop novel ways of protecting cells against such death. The death of nerve cells plays an important role in a series of neurodegenerative diseases, such as Parkinson's, Huntington's and Motor Neurone Diseases. One prevalent cause of cell death arises from the action of transmitters that normally signal between nerve cells but which, under conditions of stress and injury, ca ....Our goal is to understand the detailed process whereby nerve cells die after various stresses and injury. We aim also to develop novel ways of protecting cells against such death. The death of nerve cells plays an important role in a series of neurodegenerative diseases, such as Parkinson's, Huntington's and Motor Neurone Diseases. One prevalent cause of cell death arises from the action of transmitters that normally signal between nerve cells but which, under conditions of stress and injury, cause overstimulation of the nerve cells leading to death (excitotoxicity). Mitochondria are component of cells normally providing energy for the cell to carry out its various functions; but under stress conditions mitochondria act as controllers in cellular decision-making processes leading to cell death. Moreover, mitochondria are known to play an important role in neurodegenerative diseases, as they are a source of damaging oxygen derivatives called free radicals that cause cell injury. Mitochondria are also involved in death resulting from excitotoxicity. In order to understand the detailed mechanism of the nerve cell death process, we will use cultured nerve cells from the brains of laboratory mice, including both normal mice and those that are models of neurodegenerative disease. Injury leading to death will be induced by analogues of the transmitters that cause excitotoxicity. We will concentrate the those aspects of the death process that involve mitochondria, as this will enable us to test a range of antioxidants that can be expected to lead to new drug treatments for neuronal cell injury. Included in these compounds are novel antioxidants that are targeted to mitochondria. This project brings together the expertise in neuroscience and pharmacology of Professor Beart with the skills in biochemistry of Professor Nagley, particularly in mitochondrial and cell death research, to address this important medical research problem in a multidisciplinary manner.Read moreRead less