The Utility Of Genomics And Functional Imaging To Predict Irinotecan And Sunitinib Pharmacokinetics And Pharmacodynamics
Funder
National Health and Medical Research Council
Funding Amount
$815,733.00
Summary
Cancer patients have large differences in the way their liver breaks down anticancer drugs, leading to a poor tumor response or severe side effects. This project will be with 2 cancer drugs which can cause severe side effects. Patients will have special liver Xrays to check their liver function and have blood taken to look at DNA or genes important in drug breakdown and action. These genes and imaging may help identify patients at risk of severe toxicity or poor response and optimise drug use.
Melanoma is one of Australia s major cancer problems, but we still do not completely understand why certain people are at higher risk than others. This study is focussed on people who have a strong family history of melanoma, and is part of continuing efforts to identify the gene variants that contribute to melanoma risk. Most of the work described takes place as part of national and international collaborations to map and identify these melanoma susceptibility genes and to characterise their ef ....Melanoma is one of Australia s major cancer problems, but we still do not completely understand why certain people are at higher risk than others. This study is focussed on people who have a strong family history of melanoma, and is part of continuing efforts to identify the gene variants that contribute to melanoma risk. Most of the work described takes place as part of national and international collaborations to map and identify these melanoma susceptibility genes and to characterise their effects. Potential benefits from this research will be a better understanding of the place of genetic testing in assessing people s risk of melanoma, particularly if they have relatives with the disease, and way in which skin features like moles should be taken into account in that assessment. In addition, it is likely that better information about the genes altered in melanoma susceptibility and development will point to useful targets for development of novel anti-cancer agents.Read moreRead less
Understanding The Variation In Frontotemporal Dementia
Funder
National Health and Medical Research Council
Funding Amount
$417,750.00
Summary
Frontotemporal dementia (FTD) is one of the non-Alzheimer dementias which accounts for between 12 and 20% of all dementia and as much as 50% of early onset dementia. It is characterised by marked behavioural change and thus patients with this disease present a major management challenge. The cause of FTD is unknown and at present there is no effective treatment for the disease. There are a number of different clinical subtypes of FTD, namely behavioural variant, language variant, and FTD with mo ....Frontotemporal dementia (FTD) is one of the non-Alzheimer dementias which accounts for between 12 and 20% of all dementia and as much as 50% of early onset dementia. It is characterised by marked behavioural change and thus patients with this disease present a major management challenge. The cause of FTD is unknown and at present there is no effective treatment for the disease. There are a number of different clinical subtypes of FTD, namely behavioural variant, language variant, and FTD with motor neuron disease (FTD+MND). Similarly there are pathological subtypes of FTD (Pick's disease, frontotemporal lobar degeneration and FTD with ubiquitin-positive MND inclusions). However, there appears to be little correspondence between these two subdivisions. The purpose of this study is to investigate the pathological differences and similarities between the different clinical subtypes of FTD. Furthermore, we will investigate the changes in brain atrophy which occur over the course of the disease to allow us to understand better the initial focus of the disease. We will also evaluate the role of cellular protein changes (ubiquitin and tau) in the pathogenesis of neuronal death. This research will allow us (i) to better diagnose and characterise FTD and (ii) establish any common mechanisms of neurodegeneration in the subtypes of FTD.Read moreRead less
Convergent Regulation Of Sympathetic Neuronal Excitability By Peptide Hormones And Transmitters
Funder
National Health and Medical Research Council
Funding Amount
$498,465.00
Summary
This project will examine how hormones involved in regulating blood pressure interact with the nerves that control blood flow to the gut. We will combine electrical recordings of the activity of single nerve cells with an innovative new method of optically tracking the movements of single molecules, including hormons and neuronal messengers, that send signals to the nerve cells. Our results will reveal how blood pressure is normally maintained at healthy levels, even if we are ill.
INTER-ETHNIC DIFFERENCES IN TOLERANCE OF ANTI-CANCER DRUGS
Funder
National Health and Medical Research Council
Funding Amount
$345,894.00
Summary
In 2 previous studies we have shown that Asian cancer patients experience more side-effects than their Caucasian counterparts when treated with the same dose and schedule of treatment. This does not appear to be related to any difference in size. We wish to explain this difference as it may avoid Asian patients receiving overdoses of treatment. Possible causes include dietary and nutritional differences
Motor Unit Synchronisation And Neuromuscular Performance
Funder
National Health and Medical Research Council
Funding Amount
$198,500.00
Summary
The fine control of force is important for many everyday tasks such as writing, grasping objects between index finger and thumb, and fastening buttons. Factors that influence the ability to control force include the coordinated activation of groups of muscle fibres called single motor units. This proposal focuses on the concept that the coordinated activation of motor units is influenced by muscle activity and can impair the ability to produce finely controlled muscle contractions. The goal of t ....The fine control of force is important for many everyday tasks such as writing, grasping objects between index finger and thumb, and fastening buttons. Factors that influence the ability to control force include the coordinated activation of groups of muscle fibres called single motor units. This proposal focuses on the concept that the coordinated activation of motor units is influenced by muscle activity and can impair the ability to produce finely controlled muscle contractions. The goal of these studies is to explore the boudary conditions of the adaptive nature of the nervous system to examine how coordinated motor unit activity influences these aspects of neuromuscular performance. The outcomes of these experiments will identify if altering muscle activity influences the control of movement by altering single motor unit activity. These results will have direct application to the interpretation of abnormal movement control and tremor that is observed in certain neurological diseases such as Parkinson's disease. Furthermore, new information will be gained on the adaptability of the motor system and its role in the execution of fine motor tasks that may aid in the development of rehabilitation strategies following stroke or spinal cord injury.Read moreRead less
Investigating The Pathogenic Mechanism Of Mutations In IQSEC2 Causing Non-syndromic Intellectual Disability.
Funder
National Health and Medical Research Council
Funding Amount
$449,016.00
Summary
Intellectual disability is frequent in the population, as many as 1 in every 50 people in the world affected. Mutations in IQSEC2, an X-chromosome gene, cause intellectual disability. We will screen 1000 families with this disability for mutations in IQSEC2, building the picture of disease symptoms, contributing to informed genetic counselling. We will investigate functional impacts of these mutations in neuronal cultures, increasing our understanding of the causes of intellectual disability.
STK9, A Second Rett Syndrome Gene: Genetic And Functional Studies
Funder
National Health and Medical Research Council
Funding Amount
$468,750.00
Summary
Rett syndrome (RTT) is a devastating progressive disorder affecting motor and intellectual development. It is characterised by normal development for the first 6-12 months of life, followed by developmental regression with the loss of learned purposeful hand function, loss of acquired speech and communicative abilities, sometimes leading to the incorrect diagnosis of autism. It may be the most common cause of progressive mental retardation in girls, with an estimated prevalence in Australia of 1 ....Rett syndrome (RTT) is a devastating progressive disorder affecting motor and intellectual development. It is characterised by normal development for the first 6-12 months of life, followed by developmental regression with the loss of learned purposeful hand function, loss of acquired speech and communicative abilities, sometimes leading to the incorrect diagnosis of autism. It may be the most common cause of progressive mental retardation in girls, with an estimated prevalence in Australia of 1 per 10,000 females under the age of twelve years. It is a genetic disorder and occurs almost exclusively in females. In 1999, a gene (called MECP2) was identified which appears to be the cause of RTT in most girls and women with RTT. However, for 5 - 10% of RTT subjects, no gene change is found in the MECP2 gene, raising the possibility that other genes may also be responsible for RTT. Our research group has identified one of these genes. Known as STK9, little is known about this gene's function. Of great interest is the fact that our studies suggest that STK9 could also be a caus of intellectual disability in other patients, and with autism. The focus of this research project is to explore how common gene changes in STK9 are in a large number of children with RTT, intellectual disability and seizures, and autism with intellectual disability and seizures. Using cutting edge research technology, we will go on to study how STK9 interacts with MECP2 and other genes, in order to better understand how these genes may be detrimentally affecting brain function in girls and women with Rett syndrome and other neurological disorders. These studies will give us a greater understanding of normal brain development and function.Read moreRead less
Diseases Of Aminoacid Transport: Genetic, Molecular And Biochemical Studies
Funder
National Health and Medical Research Council
Funding Amount
$394,173.00
Summary
Aminoacids are essential building blocks of all living things. They are taken up and retained in the body by highly specific pumps on the surface of cells. By understanding the mechanisms that control aminoacids, we will not only uncover pathways common to normal biology but also shed light on mechanisms of disease in humans. Specifically, the aminoacidurias include a number of inherited diseases of aminoacid transport that result in failure of uptake and retention of particular aminoacids. Hart ....Aminoacids are essential building blocks of all living things. They are taken up and retained in the body by highly specific pumps on the surface of cells. By understanding the mechanisms that control aminoacids, we will not only uncover pathways common to normal biology but also shed light on mechanisms of disease in humans. Specifically, the aminoacidurias include a number of inherited diseases of aminoacid transport that result in failure of uptake and retention of particular aminoacids. Hartnup disease is an inherited disorder of neutral aminoacid transport that can lead to a sun-sensitive skin rash, difficulties in controlling movements and walking and other neurological symptoms including mental retardation. A major feature of Hartnup disease is its clinical variability. We have recently identified the main genetic cause for Hartnup disease, and named the gene SLC6A19. We wish to examine whether the clinical variability observed is a consequence of genetic changes and variability in SLC6A19 and other possible genes. Two other aminoacidurias to be studied are dicarboxylic aminoaciduria and iminoglycinuria; both of which are also variable in their clinical consequences ranging from normality to mental retardation. Owing to the relative rarity of these disorders, we are fortunate to have exclusive access to individuals identified by the largest neonatal screening programme for aminoacidurias in the world, based in Canada, and other clinical cohorts within Australia. We will undertake genetic testing to localise and-or confirm the gene(s) involved in these diseases for the first time anywhere and then seek to explain their clinical variability based on functional analyses. We have established a team of researchers with complementary skills from three sites comprising the Australian Aminoaciduria Consortium. Outcomes from this project should impact on the causes and possible therapies for other important medical diseases including motor neurone disease.Read moreRead less