Improving Outcomes For People With Cancer: Consultation Skills Training With Oncologists
Funder
National Health and Medical Research Council
Funding Amount
$499,070.00
Summary
Each year approximately 30,000 Australians die from cancer and 65,000 new cancers are diagnosed. Despite much research for a cure for cancer, the incidence and mortality from cancer has not changed. New treatments now cause people with cancer to live longer with the disease, so we now need to focus on efforts to optimise the quality of life of these people. Although the emotional burden on patients and families is recognized, there is a sense that this is an inevitable by-product of the disease ....Each year approximately 30,000 Australians die from cancer and 65,000 new cancers are diagnosed. Despite much research for a cure for cancer, the incidence and mortality from cancer has not changed. New treatments now cause people with cancer to live longer with the disease, so we now need to focus on efforts to optimise the quality of life of these people. Although the emotional burden on patients and families is recognized, there is a sense that this is an inevitable by-product of the disease and its management in existing clinical systems. However, this does not need to be the case. There is now ample evidence that the way that doctors interact with their patients can effect the accuracy of diagnosis and prognosis, as well as patients' satisfaction, adherence with treatment instructions and quality of life after being diagnosed with cancer. Both patient advocate groups and clinicians have called for further training for doctors to effectively manage psychosocial aspects of cancer care, however, despite this support, there have been few opportunities for such training in Australia. We have developed an innovative consultation-skills program for oncologists. So that the effectiveness of the project can be evaluated, it will be implemented as a randomised controlled trial with oncologists from major Australian cancer clinics being randomly allocated to an intervention or control group. The training program will be delivered by videoconferencing, to overcome many of the barriers that have impeded busy clinicians from participating in previous training programs. This is the first international study to use videoconferencing between remote locations for this type of consultation skills training. A variety of measures will be used to evaluate the impact of the training, including patients' quality of life, anxiety, depression and perceived needs, and oncologists' burn-out.Read moreRead less
Targeting Fungal Phospholipid Metabolism For Antifungal Drug Discovery
Funder
National Health and Medical Research Council
Funding Amount
$828,557.00
Summary
Invasive fungal infections are a serious and escalating health problem. They cause severe disease with a high death rate and are very costly to the health system. New antifungal drugs with novel properties are needed now because there are problems with current drugs. This project aims to develop potent new antifungal drugs that are effective in many fungal diseases and are well-tolerated.
Engineering Subtype Selective Inhibitors Of Voltage-sensitive Sodium Channels
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
During efforts to find new inhibitors of voltage sensitive sodium channels (VSSCs), we have discovered two new families of mu-conotoxins from Australian Conus tulipa and C. striatus that inhibit neuronal and muscle forms of the tetrodotoxin-sensitive (TTX-S) sodium channel. From these and related analogues we have identified a number of selective and highly potent inhibitors of VSSCs, opening the possibility of producing the first subtype selective TTX-S inhibitors useful in diseases such as epi ....During efforts to find new inhibitors of voltage sensitive sodium channels (VSSCs), we have discovered two new families of mu-conotoxins from Australian Conus tulipa and C. striatus that inhibit neuronal and muscle forms of the tetrodotoxin-sensitive (TTX-S) sodium channel. From these and related analogues we have identified a number of selective and highly potent inhibitors of VSSCs, opening the possibility of producing the first subtype selective TTX-S inhibitors useful in diseases such as epilepsy and stroke. These analogues also showed high selectivity for TTX-S sodium channels over a TTX-resistant (TTX-R) subtype hPN3, a key channel involved in the transmission of neuropathic pain that we recently cloned from human dorsal root ganglia. Given that TTX-S and TTX-R sodium channels have the same overall structure but differ at a relatively small number of key positions likely to affect mu-conotoxin binding, we believe it is possible to reverse engineer mu-conotoxin pharmacology in favour of the TTX-R form. This project will engineer subtype specific inhibitors of sodium channels in nerves through an understanding of how and wheremu-conotoxin bind to the sodium channel. Our long-term goal is to produce sodium channel drug candidates using m-conotoxins as templates for the development of subtype selective inhibitors of TTX-S and TTX-R sodium channels. The results of this study are designed to maximise the potential of this class of peptides as leads to the development of a new classes of therapeutics for pain, epilepsy and stroke.Read moreRead less
Haemopoiesis is the process by which cells in the blood become committed to a specific cell type, mature and proliferate. The production of blood cells is a dynamic and constant process and if dysregulated will result in a number of different diseases and-or leukemias. Using a leukemic cell line we identified two genes, Hls5 and Hls7-Mlf1, involved in red blood cell maturation. In addition, both these genes have been implicated in cancer, Hls5 functions as a tumor suppressor and Mlf1 is associat ....Haemopoiesis is the process by which cells in the blood become committed to a specific cell type, mature and proliferate. The production of blood cells is a dynamic and constant process and if dysregulated will result in a number of different diseases and-or leukemias. Using a leukemic cell line we identified two genes, Hls5 and Hls7-Mlf1, involved in red blood cell maturation. In addition, both these genes have been implicated in cancer, Hls5 functions as a tumor suppressor and Mlf1 is associated with acute myeloid leukemia. Over-expression of either gene in immature red blood cells inhibited their development; Mlf1 had quite a profound affect on cell shape and size whereas Hls5 affected biochemical pathways with a decrease in haemoglobin production. We have identified binding partners of each of the molecules. Hls5 binds to FOG 1, a regulator of the red blood cell genes. In addition, Hls5 associates with Ubc9 and PIAS-1 - molecules involved in a novel form of gene regulation called sumoylation. Hls5 also regulates GATA-1 a key protein in red cell production. Wer have recently found that Mlf1 also regulates GATA-1. Importantly, we have demonstrated that Mlf1 binds DNA and other nuclear proteins and is able to affect gene transcription. This project will use cellular and biochemical assays as well as mouse models to elucidate the mechanisms by which these genes control the function of red blood cells.Read moreRead less
IgA Mediated Activation Of FcalphaRI, An Fc Receptor And A Leukocyte Ig-like Receptor.
Funder
National Health and Medical Research Council
Funding Amount
$535,500.00
Summary
Our immune system exists to seek and destroy infections caused by bacteria and viruses (pathogens) that would grow in us. B cells in the immune system make antibody tags which attach to pathogens marking them for elimination. A special type of antibody is IgA. IgA occurs in two forms, the first is found at mucosal sites, these are membranous passages in the body, such as the lung, the gut and the genital tract. These communicate with the outside and are the major route of pathogen entry into the ....Our immune system exists to seek and destroy infections caused by bacteria and viruses (pathogens) that would grow in us. B cells in the immune system make antibody tags which attach to pathogens marking them for elimination. A special type of antibody is IgA. IgA occurs in two forms, the first is found at mucosal sites, these are membranous passages in the body, such as the lung, the gut and the genital tract. These communicate with the outside and are the major route of pathogen entry into the body. Here IgA forms a rather passive, but pathogen specific, sticky barrier to prevent microbial pathogens attaching to these large surfaces. In an everyday analogy this IgA behaves somewhat like fly-paper. This subdued response is appropriate as we are constantly exposed to micro-organisms living in our gut, or breathed into our lungs, and our immune system would make us ill if it aggressively attacked our innocuous microbial neighbours. The second type of IgA is found in the blood where it attaches to pathogens that have breached the body's barriers. These IgA tags are actively sought by white blood cells whose function is to protect the body from infection by recognising and engulfing the tagged pathogens and destroying them with killer molecules, including bleach. The IgA-Fc receptor is the sensor on the surface of white blood cells which seeks the IgA tags as they attach to pathogens. In order to survive in this hostile environment some of our pathogens, such as Staphylococcus, have their own strategies to make themselves invisible to the immune system. These strategies include cutting up the IgA tags or blocking the sensors for IgA. In this project we will study how IgA tags turn on white blood cells to destroy pathogens. We will also be looking at two Staphylococcal proteins which block up the sensor for IgA tags. Finally we are endeavouring to understand how it is the mucosal type IgA does not activate the white cells nearly as much as the IgA from the blood.Read moreRead less
Defective Tracfficking Of HERG K+ Channels: Risk Stratification In Patients With Long QT Syndrome Type 2.
Funder
National Health and Medical Research Council
Funding Amount
$483,406.00
Summary
Disturbances of the rhythm of the heartbeat are a major cause of death and disability. Due to the sudden onset and rapidity of death with cardiac arrhythmias it is important to be able to predict in advance who is most at risk. In this study we will investigate whether it is possible to develop in vitro assays to stratify risk in patients with congenital long QT syndrome type 2, an inherited arrhythmia syndrome.
Molecular Interactions Of Novel Conotoxin Inhibitors Of The Noradrenaline Transporter
Funder
National Health and Medical Research Council
Funding Amount
$392,036.00
Summary
A novel class of conotoxins (chi-conotoxins) has been discovered in the venom of an Australian cone snails, Conus marmoreus. Chi-conotoxins are the first peptide inhibitors of the noradrenaline transporter. From binding studies, it appears they act at a new site, remote from the site of action of antidepressants. This project is aimed at understanding how and where this novel class of peptide binds to the transporter. The results of this study are designed to maximise the potential of these pate ....A novel class of conotoxins (chi-conotoxins) has been discovered in the venom of an Australian cone snails, Conus marmoreus. Chi-conotoxins are the first peptide inhibitors of the noradrenaline transporter. From binding studies, it appears they act at a new site, remote from the site of action of antidepressants. This project is aimed at understanding how and where this novel class of peptide binds to the transporter. The results of this study are designed to maximise the potential of these patented peptides to be used as leads to the development of a new class of therapeutic for controlling the adverse effects of inadequate noradrenaline balance.Read moreRead less
Fc Alpha RI: Ligand Interaction And Membrane Organisation.
Funder
National Health and Medical Research Council
Funding Amount
$497,640.00
Summary
Antibodies tag invading viruses or bacteria thus marking them as foreign and targeting them for destruction by the immune system. In man the most prevelant antibody is IgA and this antibody provides protection from infecton in the blood and in the fluids at the surface of the lungs, gut and urinogenital tract. Once tagged by antibody the invading bacteria or antigen can be recogniseed white blood cells. These workhorses of the immune system use special molecules called Fc receptors on their surf ....Antibodies tag invading viruses or bacteria thus marking them as foreign and targeting them for destruction by the immune system. In man the most prevelant antibody is IgA and this antibody provides protection from infecton in the blood and in the fluids at the surface of the lungs, gut and urinogenital tract. Once tagged by antibody the invading bacteria or antigen can be recogniseed white blood cells. These workhorses of the immune system use special molecules called Fc receptors on their surface to recognise antibody tags. The receptor for IgA tags is called the Fc alpha receptor. This receptor is essential for the normal IgA-mediated protection against infection. However in a common kidney disease IgA tags accumulate in the glomerulus of the kidney stimulating white blood cells to attack and damage the kidney. This study will explain how the Fc alpha receptor recognises IgA antibody tags. It will investigate how the presentation of different forms of the receptor and different types of IgA antibody tags contributes to immunity to infection. For example one form of the receptor has a fat molecule joined to its end. We believe this may affect where the Fc alpha recptor goes to in the white blood cell membrane and whether it can activate the white blood cell to fight the invading microorganism.Read moreRead less
Dissecting The Divisome: Development Of Antibacterial Agents That Inhibit Bacterial Cytokinesis
Funder
National Health and Medical Research Council
Funding Amount
$504,097.00
Summary
Infectious diseases accounted for 25-30% of the estimated 54 million deaths worldwide in 1998. Unfortunately, the recent spread of antibiotic resistant bacteria from hospitals into the community has coincided with a marked downturn in the rate of development of new antibiotics. Thus, there is an urgent need to develop new antimicrobial agents. The aim of this project is to provide essential groundwork for the development of new antimicrobials that inhibit bacterial cell division.
Structure, Function And Regulation Of Human Cytosolic Sulfotransferases
Funder
National Health and Medical Research Council
Funding Amount
$265,500.00
Summary
The sulfotransferase family of enzymes serve an important role in the metabolism of drugs and foreign chemicals. They also metabolise a range of chemicals that are normally present in the body such as hormones and substances that are involved in brain function (neurotransmitters). Observations from clinical studies suggest that differences in sulfotransferases activities may be a causal factor in the incidence of certain types of cancer and neurodegenerative diseases. Recent advances in understa ....The sulfotransferase family of enzymes serve an important role in the metabolism of drugs and foreign chemicals. They also metabolise a range of chemicals that are normally present in the body such as hormones and substances that are involved in brain function (neurotransmitters). Observations from clinical studies suggest that differences in sulfotransferases activities may be a causal factor in the incidence of certain types of cancer and neurodegenerative diseases. Recent advances in understanding the molecular biology of these enzymes have shown us that multiple forms of sulfotransferase existed within the body. In this area my laboratory has been at the forefront of the cloning and characterisation of these enzymes. Indeed, we were the first laboratory to clone the major human sulfotransferase (SULT1A3) responsible for the metabolism of brain neurotransmitters. We have also used new technology to determine the shape of this important enzyme. At the time of writing my laboratory has characterised a total seven human sulfotransferases but unlike SULT1A3, our knowledge of the functional significance of the other six sulfotransferase is poorly understood. Further, our knowledge of what regulates the amount of sulfotransferase in different tissues is practically nonexistent. The thrust of this project is to extend our studies on the physiological function of these enzymes and also through the use of molecular biology techniques understand what controls the level of their expression in different human tissues. This knowledge will provide a basis for understanding the role of sulfotransferases play in drug and chemical metabolism. It will also aid our understanding of their role in hormone and neurotransmitter metabolism and help determine whether they are involved in such diseases as cancer and neurodegenerative diseases.Read moreRead less