Roles Of The Peptide Hormone, Ghrelin, In The Spinal Cord
Funder
National Health and Medical Research Council
Funding Amount
$414,326.00
Summary
This study investigates the control of internal organs of the body, the heart, blood vessels, intestine and bladder. We have made the new and surprising discovery that ghrelin, previously known to be a hormone, is probably also a neurotransmitter in the spinal cord. This raises the possibility that drugs that act on ghrelin receptors in the spinal cord could be used to treat high blood pressure or other problems of internal organs.
Adipose Triglyceride Lipase: Regulation And Implications For The Aetiology Of Insulin Resistance
Funder
National Health and Medical Research Council
Funding Amount
$323,453.00
Summary
Obese individuals have elevated fat levels in the blood and muscle, which contributes to the development of other diseases such as type 2 diabetes. A newly discovered protein named adipose triglyceride lipase (ATGL) is essential for fat breakdown. This project aims to identify how ATGL operates and determine whether defective ATGL function leads to type 2 diabetes. These studies will assist in the development of strategies aimed at reducing fatty acids in blood and muscle.
DNA-binding proteins regulate gene expression to co-ordinate our development and physiology. These proteins operate by recognizing specific control sequences in target genes and turning these genes on or off. It may be possible to artificially regulate specific genes to treat certain inherited disorders. One of the most common genetic diseases worldwide is inherited haemoglobinopathy. Mutations in the adult beta haemoglobin gene cause diseases such as sickle cell anaemia and beta thalassaemia. T ....DNA-binding proteins regulate gene expression to co-ordinate our development and physiology. These proteins operate by recognizing specific control sequences in target genes and turning these genes on or off. It may be possible to artificially regulate specific genes to treat certain inherited disorders. One of the most common genetic diseases worldwide is inherited haemoglobinopathy. Mutations in the adult beta haemoglobin gene cause diseases such as sickle cell anaemia and beta thalassaemia. These diseases can be seriously debilitating or lethal and often require lifelong treatment. Current treatments (such as repeated blood transfusion and subsequent iron chelation therapy) are demanding on the patient, expensive, and in the long run can be inneffective. Proposed future treatments involve reactivating normally silent haemoglobin genes (such as foetal haemoglobin) to compensate for the absence of adult beta haemoglobin. We have been studying a DNA-binding protein termed BKLF. We have shown that BKLF turns genes off and in particular we have shown using mammalian model systems that BKLF turns off the foetal haemoglobin gene. Inhibiting BKLF action therefore becomes an important goal, as this might lead to a reactivation of foetal haemoglobin to alleviate sickle cell anaemia and beta thalassaemia. We are seeking to understand the molecular mechanisms by which BKLF silences gene expression, to identify other proteins with which it operates, and to define their activities, in an effort to identify the best ways of inhibiting BKLF's action. Ultimately, studies on defined model genes such as the haemoglobin genes should elucidate general principles of gene regulation that may be useful in controlling gene expression in additional therapeutic or experimental contexts.Read moreRead less
Characterisation Of A Novel Porphyromonas Gingivalis Regulatory Protein That Controls Virulence Related Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$569,620.00
Summary
In this study we will characterise the manner in which genes essential for the virulence of Porphyromonas gingivalis, a bacterium associated with chronic periodontitis, are regulated. This will provide information on how this bacterium causes disease and may offer opportunities for the development of new treatment strategies.
Transcriptome Profiling Of The Human Pathogen Schistosoma Japonicum
Funder
National Health and Medical Research Council
Funding Amount
$257,560.00
Summary
The parasitic disease, schistosomiasis, caused by human bloodflukes of the genus Schistosoma, is a major public health issue in Africa, Latin America and South East Asia. Current control methods are far from ideal, and a comprehensive understanding of the genetic mechanisms which allow schistosomes to grow, develop and survive within their hosts affords the best prospect for identifying new drug and vaccine targets. Microarray technology allows simultaneous monitoring of thousands of different g ....The parasitic disease, schistosomiasis, caused by human bloodflukes of the genus Schistosoma, is a major public health issue in Africa, Latin America and South East Asia. Current control methods are far from ideal, and a comprehensive understanding of the genetic mechanisms which allow schistosomes to grow, develop and survive within their hosts affords the best prospect for identifying new drug and vaccine targets. Microarray technology allows simultaneous monitoring of thousands of different genes, and to determine where and when they are active, thus placing the mass of data generated by genome sequencing programs into a biological and functional context. Microarrays provide a unique, cutting-edge, tool for investigating schistosome biology. We have fabricated a microarray representing some 20,000 schistosome genes. We will use this resource to perform large scale monitoring of schistosome gene expression during the parasite's complex life cycle, targetting the regionally important Asian schistosome, Schistosoma japonicum, for study. This will provide the single largest insight into the genetic changes that occur during schistosome development, will greatly further our understanding of the adaptations needed for the growth, development and survival of the parasite, and will identify genes involved in key biological processes, all of which may be exploitable for future interventions and treatments.Read moreRead less
Towards Novel Therapies For Scabies: Functional Analysis Of Sarcoptes Scabiei Aspartic Proteases.
Funder
National Health and Medical Research Council
Funding Amount
$328,231.00
Summary
Scabies is a significant problem in disadvantaged populations worldwide, particularly Australian Aboriginal communities where up to 65% of people can be affected. Our research will investigate the role that aspartic proteases play in the interaction of the mite with its host. We will examine methods of interfering with the function of these proteins with the aim of designing new, effective treatments for scabies.
Sensory Neuronal Pathways From The Lower Genital Tract Of Females
Funder
National Health and Medical Research Council
Funding Amount
$397,224.00
Summary
Many women experience severe debilitating pain upon normally innocuous contact with their genitalia. The causes of this pain are unknown. Therefore, this project will use a suite of sophisticated microscopic and electrical recording techniques to identify the neural pathways that transmit sensation, including pain, from the female lower genital tract. Our new data will help create a rational basis for understanding and treating the physical basis of genital pain in women.
Identification And Characterisation Of Human Telomerase Holoenzyme Components
Funder
National Health and Medical Research Council
Funding Amount
$325,091.00
Summary
DNA is packaged into linear structures - chromosomes - that have two ends, called telomeres. When cells proliferate, their telomeres normally shorten slightly, and this ultimately limits the number of times cells can proliferate. This limitation is thought to contribute to ageing. Some tissues normally have a high rate of cell turnover (for example in the bone marrow which is constantly producing large numbers of new blood cells), and therefore a need for very extensive cellular proliferation. I ....DNA is packaged into linear structures - chromosomes - that have two ends, called telomeres. When cells proliferate, their telomeres normally shorten slightly, and this ultimately limits the number of times cells can proliferate. This limitation is thought to contribute to ageing. Some tissues normally have a high rate of cell turnover (for example in the bone marrow which is constantly producing large numbers of new blood cells), and therefore a need for very extensive cellular proliferation. In these tissues, an enzyme called telomerase slows down (but does not completely prevent) the rate of telomere shortening by replacing some of the DNA that is lost as a result of proliferation. Telomerase is a complex enzyme with a number of subunits. In the past few years, it has started to become clear that inherited deficiencies of some of these subunits cause diseases in which cellular proliferation starts to fail at a young age. These patients typically die of bone marrow failure. In contrast to conditions where there is telomerase deficiency, the great majority of cancers have inappropriately high levels of telomerase activity which allow cancer cells to continue dividing without limit. Telomerase is therefore regarded as a very promising target for new cancer treatments. In view of the importance of telomerase to human health, it may seem very surprising that we do not yet know all of its subunits. The reason for this is that, even in telomerase-positive cancer cells, the amount of telomerase present is vanishingly small which has made it impossible so far to obtain sufficient quantities for even the most sensitive analytical techniques. We are using very large numbers of human cells grown in a bioreactor, and have devised a highly efficient method for purifying telomerase from them. We will analyse the purified telomerase by contemporary mass spectroscopy techniques, identify all of the subunits, and characterise their contribution to telomerase function.Read moreRead less
Genetic Variation And Host-parasite Interactions Of Sarcoptes Scabiei
Funder
National Health and Medical Research Council
Funding Amount
$294,536.00
Summary
Scabies is a disease of skin caused by the burrowing of the 'itch' mite Sarcoptes scabiei. Although up to 45 different host species can be infested by this mite, this organism is currently classified as a single species existing as multiple strains or varieties. Previous studies have failed to identify any structural differences between host-associated populations, suggesting a single gene pool. Our recent molecular study of scabies in people and dogs, from Aboriginal communities in the Northern ....Scabies is a disease of skin caused by the burrowing of the 'itch' mite Sarcoptes scabiei. Although up to 45 different host species can be infested by this mite, this organism is currently classified as a single species existing as multiple strains or varieties. Previous studies have failed to identify any structural differences between host-associated populations, suggesting a single gene pool. Our recent molecular study of scabies in people and dogs, from Aboriginal communities in the Northern Territory and the North and South Americas, using DNA fingerprinting techniques, suggested mites cluster by host species with no evidence of cross-transmission. However although this data seems to suggest that these sub-species deserve species status, another molecular study suggests Sarcoptes is a single species, presumably a result of interbreeding. Understanding interbreeding between populations is important in the control of the disease and in controlling resistance to acaricides. We wish to further characterise the genetic separation of different 'strains' or populations of mites by studying the evolutionary gene flow between host-associated populations. We will use a mitochondrial DNA marker that will clarify fine scale transmission processes and more clearly delineate the biological species status of S. scabiei. Recent in vitro data and clinical evidence in a patient with severe crusted scabies indicated resistance to ivermectin, the treatment of choice for these patients. We will investigate the role and genetic mechanisms of ivermectin resistance. This is important for future control programs, as acaricide resistance can spread rapidly in parasite populations.Read moreRead less