Identification And Function Of Posttranslational Modifications In The Dioxin Receptor/Arnt Transcription Factor
Funder
National Health and Medical Research Council
Funding Amount
$448,500.00
Summary
Polycyclic aromatic hydrocarbons (PAHs) are prevalent environmental pollutants which cause a wide range of deleterious health effects. Metabolic activation of PAHs occurs primarily through a set of intracellular oxidising enzymes which are induced by the presence of PAHs. The dioxin receptor is a gene regulatory protein that is pivotal in the metabolic pathway as it links the presence of contaminating PAHs to induction of the enzymes responsible for initiating their metabolism. While in many cas ....Polycyclic aromatic hydrocarbons (PAHs) are prevalent environmental pollutants which cause a wide range of deleterious health effects. Metabolic activation of PAHs occurs primarily through a set of intracellular oxidising enzymes which are induced by the presence of PAHs. The dioxin receptor is a gene regulatory protein that is pivotal in the metabolic pathway as it links the presence of contaminating PAHs to induction of the enzymes responsible for initiating their metabolism. While in many cases PAHs are oxidised to compounds which are water soluble and excretable (and therefore harmless), some substrates, such as benzo[a]pyrene found in cigarette smoke, can become inadvertently transformed into carcinogens. Other pollutants such as dioxin are resistant to metabolism and are extremely toxic. We have an ongoing interest in deciphering the biochemical pathways which lead to aberrant metabolism, and as such are studying the mechanistic role of the dioxin receptor in this process.Read moreRead less
Characterising Protein And Membrane Changes In Age-related Cataract Lenses.
Funder
National Health and Medical Research Council
Funding Amount
$441,624.00
Summary
Cataract is the major cause of blindness worldwide. At present the only treatment for cataract, is surgery. This, however, is associated with complications (e.g. posterior capsule opacification), is expensive (a major component of the Health budget) and cannot keep pace with the incidence of cataract in developing nations. In addition, due to the greying of the community , this problem will be of increasing importance in the future. For prevention, we need to understand why cataract develops.
Deciphering Posttranslational Codes Of The Dioxin Receptor
Funder
National Health and Medical Research Council
Funding Amount
$540,083.00
Summary
The dioxin receptor (DR) is a protein which protects human cells by binding xenobiotics, ie foreign or anti-nutritional chemicals found in food sources and the general environment. When these chemicals bind the DR, it becomes an active gene regulatory protein, turning on genes that are involved in breakdown and excretion of the xenobiotics. Recently it has been found that the DR performs other important functions which are unrelated to xenobiotic breakdown. These include blood vessel development ....The dioxin receptor (DR) is a protein which protects human cells by binding xenobiotics, ie foreign or anti-nutritional chemicals found in food sources and the general environment. When these chemicals bind the DR, it becomes an active gene regulatory protein, turning on genes that are involved in breakdown and excretion of the xenobiotics. Recently it has been found that the DR performs other important functions which are unrelated to xenobiotic breakdown. These include blood vessel development in the embryonic liver and hormone production during the estrous cycle. These observations imply that natural physiological mechanisms also exist for activating the DR, providing it with a separate code to perform these innate functions. A number of man-made chemicals, such as dioxins and PCBs, are especially good at activating the DR. However, they have chlorinated chemical structures, which are not broken down by the protective system. This creates a wide range of severe toxic responses. It has been established that toxicities result from persistent hyperactivation of the DR, but how this hyperactivation induces the toxic outcomes is not known. As the DR has roles in early development and estrogen production, this project will investigate how the DR becomes activated to perform these functions. Our initial experiments have shown that the DR can be activated by normal cell signalling systems, which induce distinct modifications (a distinct code) to the protein. We are comparing this code of modifications to those induced by xenobiotics which are able to be broken down, and dioxins which are resistant to breakdown. We hypothesise that dioxins will give an excessive code of activating modifications, resulting in uncontrolled regulation of genes used in both the developmental and xenobiotic breakdown pathways. We will explore the hypothesis that this gross loss of gene regulatory control underpins the multifarious toxicities of dioxin poisoning.Read moreRead less
Impact Of The Extension Of The Sydney Light Rail System On The Prevalence Of Physical Activity Participation
Funder
National Health and Medical Research Council
Funding Amount
$105,647.00
Summary
Regular participation in physical activity is associated with a range of physical and mental health benefits in adults, including reduced risk for cardiovascular disease, non-insulin dependent diabetes, overweight, hypertension, osteoporosis, some cancers and anxiety and depression. Regular participation in physical activity also improves the ability to meet the demands of work and to engage in leisure activities. Approximately half of all adult Australians are insufficiently active to gain the ....Regular participation in physical activity is associated with a range of physical and mental health benefits in adults, including reduced risk for cardiovascular disease, non-insulin dependent diabetes, overweight, hypertension, osteoporosis, some cancers and anxiety and depression. Regular participation in physical activity also improves the ability to meet the demands of work and to engage in leisure activities. Approximately half of all adult Australians are insufficiently active to gain the many health benefits associated with participation in regular physical activity. Modification of the physical environment is one avenue through which the prevalence of physcial activity participation might be increased. More specifically, there has been considerable speculation about the role of public transportation systems in increasing the proportion of adults who are adequately physically active, but no empirical evidence is available. This study will employ a quasi-experimental design to determine if the extension of the Sydney Light Rail System to Lilyfield results in an increase in the prevalence of physical activity (primarily walking) in the affected area, in comparison with a demographically similar area which is not affected by the light rail extension.Read moreRead less
Understanding The Role Of Human Lens UV Filters In Age-Related Cataract
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Cataract is the most common cause of blindness worldwide, The cause of cataract is currently unknown and the only treatment available at present is surgery. This represents a huge burden on the Health budgets of all developed nations, including Australia. It has been estimated that if a treatment could be developed that simply delayed the onset of cataract by 10 years, the need for surgery would be halved. The savings to the Health budget in the USA alone would be approximately $2 billion (US). ....Cataract is the most common cause of blindness worldwide, The cause of cataract is currently unknown and the only treatment available at present is surgery. This represents a huge burden on the Health budgets of all developed nations, including Australia. It has been estimated that if a treatment could be developed that simply delayed the onset of cataract by 10 years, the need for surgery would be halved. The savings to the Health budget in the USA alone would be approximately $2 billion (US). We believe, on the basis of our previous research, that human lens UV filter compounds play a major role in the protein modification that is the hallmark of age-related cataract and indeed may be the key factor in precipitating cataract. This proposal seeks to confirm this hypothesis. If this theory is confirmed, it opens the door to pharmacological intervention for cataract by, for example, treating patients (or possibly all people in middle age) with drugs that inhibit the synthesis of the UV filter compounds.Read moreRead less
Remodelling Of Bacterial Outer Membranes: Implications For Vaccine Development.
Funder
National Health and Medical Research Council
Funding Amount
$558,189.00
Summary
We have identified proteins located in bacteria that are responsible for growth and the transport of essential nutrients. We will use a combination of bacterial genetics, protein biochemistry and immunological techniques to fully characterize these proteins. This strategic knowledge has direct implications for vaccine development and National security, since similar species of bacteria were amongst the first biological weapons.
Extension Of The Calcium Intake Fracture Outcome Study
Funder
National Health and Medical Research Council
Funding Amount
$272,025.00
Summary
Osteoporosis is a largely preventable disease yet 1 in 10 Australians have osteoporosis. Every year >64,000 osteoporotic fractures occur, which is one every 8.1 minutes and women are three times as likely to have the disease than men. The Bone and Calcium Research Group at the University of Western Australia, is studying how to prevent osteoporosis in elderly women. This study is called the Calcium Intake Fracture Outcome Study or CAIFOS. During 1998, 1,500 women were recruited to study wheth ....Osteoporosis is a largely preventable disease yet 1 in 10 Australians have osteoporosis. Every year >64,000 osteoporotic fractures occur, which is one every 8.1 minutes and women are three times as likely to have the disease than men. The Bone and Calcium Research Group at the University of Western Australia, is studying how to prevent osteoporosis in elderly women. This study is called the Calcium Intake Fracture Outcome Study or CAIFOS. During 1998, 1,500 women were recruited to study whether a daily calcium supplement for 5 years helps to prevent fractures compared to a diet without a supplement. To do this only half of the women were given calcium supplements and the other half were given matched placebo tablets. Each year the study participants are reviewed and asked whether or not they have broken any bones and have other measurements to monitor their bone health and overall health. The subjects are entering their last year of treatment and will finish the study during 2003. At this appointment all subjects will undergo the same series of measurements that they had at the beginning of the study to determine whether or not they have fractured any bones, improved their bone mass and overall health during the treatment stage. The main outcome of the study is to determine whether calcium is useful as a supplement to prevent osteoporotic fracture in elderly women. If this study finds that fewer women fractured in the calcium treated group compared to the non treated group, given that both groups were similar to begin with, we can say that supplementation with calcium prevents fractures. Thus, public health messages about preventing osteoporosis will be able to direct the community to take supplements to prevent a disease that creates pain and disability in later life. The advantage of this study is that it is studying other aspects of these women health, so we can determine whether the calcium is safe to use and improves people's quality of life.Read moreRead less
GPI Anchored Forms Of The Dengue Virus NS1 Protein: Production And Role In Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$203,448.00
Summary
Dengue viruses are carried by mosquitoes and infect millions of people around the world, particularly in tropical countries of SE Asia, Central and South America, Africa and recently in Australia (North Queensland and NT). There is no vaccine or drug available for preventing or treating the infections, which are characterised by severe illness that involves inflammation and fevers that can sometimes be fatal. This study focuses on an unusual form of a dengue virus protein (called NS1) which we h ....Dengue viruses are carried by mosquitoes and infect millions of people around the world, particularly in tropical countries of SE Asia, Central and South America, Africa and recently in Australia (North Queensland and NT). There is no vaccine or drug available for preventing or treating the infections, which are characterised by severe illness that involves inflammation and fevers that can sometimes be fatal. This study focuses on an unusual form of a dengue virus protein (called NS1) which we have identified. We plan to study the role that this protein plays in the more severe and often fatal forms of dengue infection (dengue haemorrhagic fever and dengue shock syndrome). In these more severe and life threatening forms of dengue the blood vessels of these patients become leaky. It is thought that this is caused by the secretion of certain chemicals (cytokines) from infected cells. We have shown that dengue infected human cells, which have the unusual form of NS1 protein on their surface, are capable of being activated by antibodies. Antibodies are proteins which are produced by the human body to fight infection. We aim to study whether cytokines are secreted from infected human blood cells activated in this way and whether these cytokines cause blood vessels to become leaky. We will also study how the virus produces this variant form of NS1 in the two host species that the virus infects; mosquito and human. These studies will increase our understanding of dengue virus infection and will provide valuable information concerning the role that this unusual form of the degue virus protein NS1 plays in the severe forms of dengue fever; dengue haemorrhagic fever and dengue shock syndrome.Read moreRead less
Chromosomes are structures that carry genes in all our cells. Every human cell has 46 chromosomes. In the nucleus of eukaryotic cells, DNA is highly folded and compacted with specific proteins into a dynamic polymer called chromatin. Gene expression, chromosome division, DNA replication, and repair all act, not on DNA alone, but on this chromatin template. The discovery that enzymes can (re)organise chromatin into accessible and inaccessible configurations revealed mechanisms that considerably e ....Chromosomes are structures that carry genes in all our cells. Every human cell has 46 chromosomes. In the nucleus of eukaryotic cells, DNA is highly folded and compacted with specific proteins into a dynamic polymer called chromatin. Gene expression, chromosome division, DNA replication, and repair all act, not on DNA alone, but on this chromatin template. The discovery that enzymes can (re)organise chromatin into accessible and inaccessible configurations revealed mechanisms that considerably extend the information potential of the genetic code. In addition, it is now established that chromatin structural features can influence gene expression. In vitro studies support a model in which chromatin functions as a barrier for the access to DNA. Therefore this organization has to be tighly regulated and dynamic to allow the protein-DNA interactions critical for nuclear functions. Importantly genome organisation provides in addition to genetic information another layer of information, so called epigenetic, which by definition means that it is stably inherited throughout cellular divisions, yet it is not encoded genetically. Thus each cell type will display a specific epigenome. We have recently constructed small human minichromosomes, which are much easier to study than the much larger normal chromosomes. The present project proposes to define the epigenetic feature across an entire human chromosome using our minichhromosomes as working models. The outcome will be a significant gain in our knowledge on the processes underlying epigenetic regulation, the organisation of specialised chromatin domain, and behaviour of the chromosomes.Read moreRead less