Dissecting The Molecular Mechanisms Behind Actin Filament Disassembly - An Essential Process In Malaria Parasite Cell Movement
Funder
National Health and Medical Research Council
Funding Amount
$311,860.00
Summary
The malaria parasite’s survival is reliant on efficient cell movement - a process that depends on the remodeling of the parasite actin cytoskeleton. The aim of this project is to understand how the actin cytoskeleton is disassembled when the parasite moves and to dissect the role of a key parasite protein, PfADF1, in the process. This project will elucidate fundamental insights into a key aspect of malaria parasite biology and, significantly, will shed light on how parasite movement can be inhib ....The malaria parasite’s survival is reliant on efficient cell movement - a process that depends on the remodeling of the parasite actin cytoskeleton. The aim of this project is to understand how the actin cytoskeleton is disassembled when the parasite moves and to dissect the role of a key parasite protein, PfADF1, in the process. This project will elucidate fundamental insights into a key aspect of malaria parasite biology and, significantly, will shed light on how parasite movement can be inhibited.Read moreRead less
Significance Of Low-level Mosaicism To Intellectual Disability In Paediatric Disorders
Funder
National Health and Medical Research Council
Funding Amount
$483,402.00
Summary
My vision for the next 4 years is to improve outcomes for children and their families with inherited disorders associated with intellectual disability (ID) and autism through earlier diagnosis and intervention. This is of great importance with annual costs of ID close $14.72 billion to the Australian health system, and missed or delayed diagnoses being a significant problem, as ID is found in 1.7% of births, where a specific cause is currently identified in less than half.
Risk Factors Associated With The Expansion Of CGG Repeat Sequences In The FMR1 (fragile X) Gene: A Study In Tasmania
Funder
National Health and Medical Research Council
Funding Amount
$246,020.00
Summary
This study will identify the risk factors that lie in an individual's DNA profile for a disease called fragile X syndrome. This disease is the most common form of intellectual disability that runs in families caused by an unusual form of change in a particular gene called FMR1, whereby a very short sequence of DNA in a gene expands by repeating itself to such an extent that once it reaches a certain size the whole gene stops working and the disease occurs. The expansion in the gene is not unifor ....This study will identify the risk factors that lie in an individual's DNA profile for a disease called fragile X syndrome. This disease is the most common form of intellectual disability that runs in families caused by an unusual form of change in a particular gene called FMR1, whereby a very short sequence of DNA in a gene expands by repeating itself to such an extent that once it reaches a certain size the whole gene stops working and the disease occurs. The expansion in the gene is not uniform across the generations, and only occurs when passed on from the mother to her offspring. However, many females carrying only a short sequence may pass on, for unknown reasons, either a large expanded sequence leading to disease, or one similar in size to her own. This complexity in the progression of the number of CGG repeats means that there is a relatively large number of mothers, ~1 in 300, who are quite normal but at risk of having an affected offspring. The factors that trigger this expansion in the DNA are presently not well understood, but a number of genetic markers in the FMR1 gene have been implicated. This study will assess the contribution of an array of these genetic markers in determining the risk of expansion of the short repeat from mother to offspring and hence the risk of fragile X. Conducting this study in Tasmania has two advantages. First, by having access to genealogical records that permit the linking of fragile X families we shall be able to identify common predisposing factors of fragile X more accurately. Second, by testing the whole population with intellectual disability in one State of manageable size we shall obtain an unbiased estimate of the prevalence of fragile X.Read moreRead less
Towards Targeting The Endosome In Neurodegenerative Disease
Funder
National Health and Medical Research Council
Funding Amount
$601,959.00
Summary
Mutations and dysregulation of the SNX27-retromer protein platform are strongly linked to Alzheimer’s disease (AD) and Parkinson’s disease (PD). This research program will determine how SNX27-retromer interacts with key molecules associated with AD and PD, the outcomes of which be significantly improved understanding of how mutations in these proteins cause disease, and a necessary molecular framework for future therapeutic targeting.
Characterization Of A Novel Human X-linked Gene RBMX, A Candidate For X-linked Mental Retardation
Funder
National Health and Medical Research Council
Funding Amount
$356,870.00
Summary
We recently discovered a novel gene (which we have called RBMX for RNA-binding protein, X chromosome) on the human X chromosome. Its function is quite unknown, but it is active in all tissues, and it has changed very little in evolution, so we think it must have an important function in human development. Genes with a similar sequence bind to RNA and convert it to its final active form, so RBMX may have a similar role. Other RNA-binding proteins are active in the brain, so we suspect that RBMX m ....We recently discovered a novel gene (which we have called RBMX for RNA-binding protein, X chromosome) on the human X chromosome. Its function is quite unknown, but it is active in all tissues, and it has changed very little in evolution, so we think it must have an important function in human development. Genes with a similar sequence bind to RNA and convert it to its final active form, so RBMX may have a similar role. Other RNA-binding proteins are active in the brain, so we suspect that RBMX may be involved in brain development and learning. The RBMX gene is also interesting because it has a copy called RBMY on the human Y chromosome, which is thought to have a critical (unknown) function in sperm production. Of particular note is our finding that RBMX maps to the long arm of the human X chromosome at Xq26. This is a region that contains several inherited mental retardation syndromes called X linked mental retardation (XLMR) which are carried by females and manifest in males. At least eight XLMR syndromes have been mapped to human Xq26. Several of the syndromes have characteristic skeletal and facial abnormalities, as well as a range of other anomalies.. We will completely characterise the human RBMX gene. As well as giving us fresh clues to its function, this will allow us to make a mouse strain that lacks the gene (knockout) so we can see whether it is critical for life, and if it is involved in brain development and learning. Identification of an XLMR gene coding for an RNA binding protein will shed light on the role of RNA metabolism in the brain, and the effect of disruptions of RNA processing on mental function. We will then screen the RBMX gene in families with XLMR syndromes, to look for RBMX mutations in patients which may cause XLMR. If mutations in RBMX cause one or more XMLR phenotypes, it will be possible to use this knowledge to diagnose the condition and detect carriers.Read moreRead less
Prevalence And Characterisation Of FMR1 Gene's Premutation Carriers Amongst Older Males Presenting With Tremor/ataxia
Funder
National Health and Medical Research Council
Funding Amount
$199,450.00
Summary
The study concerns a novel form of progressive neurological disorder associated with tremor and body imbalance occurring in older males and caused by a small expansion of the trinucleotide (CGG) repeat in a fragile X (FMR1) gene. This expansion is termed 'premutation', in contrast with the full mutation, where a large expansion of the CGG repeat in this gene causes Fragile X Syndrome, a common form of intellectual disability. While brain anomaly in the full mutation is caused by a deficit of the ....The study concerns a novel form of progressive neurological disorder associated with tremor and body imbalance occurring in older males and caused by a small expansion of the trinucleotide (CGG) repeat in a fragile X (FMR1) gene. This expansion is termed 'premutation', in contrast with the full mutation, where a large expansion of the CGG repeat in this gene causes Fragile X Syndrome, a common form of intellectual disability. While brain anomaly in the full mutation is caused by a deficit of the FMR1 specific protein product (FMRP), the pathways from premutation to a neurological disorder are unknown. In this disorder, neurological dysfunction is associated with brain atrophy visible in magnetic resonance (MRI) images. Molecular studies showed increased levels of 'messenger' RNA (mRNA), which indicates overexpression of FMR1 gene . Our own study showed significantly increased (41.7%) prevalence of neurological involvement in male premutation carriers aged >50, compared with age-matched norms. Moreover, a screening of patients with two neurological disorders associated with tremor showed a significant increase of premutation carriers (5%- 22%). The aim of this study is to test hypotheses about the association of late-onset neurological disorders of unknown cause presenting tremor and imbalance, with a fragile X premutation in males, by screening for the presence of this premutation; and then conducting a full assessment of the identified premutation carriers, including detailed neurological, neuropsychological and MRI tests, to establish the spectrum of neurological involvement. This involvement will be correlated with the molecular (DNA, mRNA, FMRP) findings. The results will contribute to understanding the mechanisms of neurological involvement caused by this premutation. Moreover, estimation of the prevalence of this premutation in relevant neurological disorders will impact on standard diagnostic, and possibly future treatment approaches in neurology clinics.Read moreRead less
Prevalence And Genetic Mechanisms Of Neurological And Gynaecological Changes In Women Carrying Small FMR1 Expansions
Funder
National Health and Medical Research Council
Funding Amount
$411,895.00
Summary
Fragile X syndrome is one of the commonest genetic forms of mental retardation. The abnormal gene is passed from mothers to their sons or daughters, on their X chromosome. The gene abnormality is unstable, tending to worsen each time it is passed on. But if this gene abnormality is passed from fathers to their daughters, it does not worsen. Therefore, grandfathers of the affected children on their mother's side, as well as the mothers, may carry a mildly abnormal gene (a premutation), insufficie ....Fragile X syndrome is one of the commonest genetic forms of mental retardation. The abnormal gene is passed from mothers to their sons or daughters, on their X chromosome. The gene abnormality is unstable, tending to worsen each time it is passed on. But if this gene abnormality is passed from fathers to their daughters, it does not worsen. Therefore, grandfathers of the affected children on their mother's side, as well as the mothers, may carry a mildly abnormal gene (a premutation), insufficient to cause mental retardation. However, it has recently been discovered that these grandfathers may develop a syndrome (FXTAS) of tremor, incoordination, slowness of movements and mild dementia in their later years. Women were thought to be protected, as they carry TWO X chromosomes, one of which is normal even if the other has a premutation. But very recent reports suggest that they may also develop the FXTAS syndrome, as well as early menopause. This study aims to see how common and severe these abnormalities are in women who carry the premutation, using clinical, MRI and electronic measurements, and to relate the abnormalities to the severity of the gene malfunction and familial predisposition.Read moreRead less