Defining FMR1 And SNRPN Epigenetic Signatures Associated With Neurodevelopmental Disorders
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Fragile X Syndrome and imprinting disorders such as Prader-Willi Syndrome and Angelman Syndrome are characterised by variable penetrance for intellectual disability, motor delay and autism spectrum disorder. This project aims to investigate the prognostic value of using blood-based biomarker tests and sensitive neuroscience informed measures to predict risk and severity of neuropsychological problems in children affected by these disorders.
Functional Significance Of MeCP2 Target Genes In The Pathogenesis Of Rett Syndrome.
Funder
National Health and Medical Research Council
Funding Amount
$476,815.00
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 is a genetic disorder and contributes to a substantial proportion of girls with severe mental retardation. In 1999, a g ....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 is a genetic disorder and contributes to a substantial proportion of girls with severe mental retardation. In 1999, a gene (called MECP2) was identified which appears to be the cause of RTT in at least 80% of affected girls and women. Now that the gene responsible for many cases of RTT has been found, new questions are being asked. Why are the effects of these mutations restricted to the brain? Which other genes might play a role in the symptoms seen in RTT? The focus of this research project is to examine these 2 questions. Using new research techniques, we have identified genes that are themselves secondarily affected by mutations in the MECP2 gene. We wish to study these genes in more detail, with the aim being to gain a greater understanding of how these genes contribute to the onset of impaired brain function in girls and women with RTT. These insights are essential foundations for the development and evaluation of new and more specific therapies for this as yet incurable disorder.Read moreRead less
Cellular Mechanisms Controlling Neural Crest Cell Migration Along The Developing Gut
Funder
National Health and Medical Research Council
Funding Amount
$368,895.00
Summary
Within the wall of the gut, there are a large number of neurons, probably more than are in the spinal cord. These enteric neurons play an essential role in controlling a number of gut functions including peristalsis (the propulsion of contents along the gut). Most of the neurons in the gut, including those in the large intestine, arise from precursors that emigrate from the hindbrain, and then migrate into and along the gastrointestinal tract during development. The colonization of the gut by ne ....Within the wall of the gut, there are a large number of neurons, probably more than are in the spinal cord. These enteric neurons play an essential role in controlling a number of gut functions including peristalsis (the propulsion of contents along the gut). Most of the neurons in the gut, including those in the large intestine, arise from precursors that emigrate from the hindbrain, and then migrate into and along the gastrointestinal tract during development. The colonization of the gut by neuron precursors takes 5 days in mice and 6 weeks in humans. Studies of the mechanisms controlling the migration of neuron precursors along the gut have provided fundamental information about cell migration in general. Genetic studies in humans and mice have identified some of the genes that are necessary for the migration of neuron precursors along the gastrointestinal tract, but for some of the key genes, their precise role is unknown. We have recently developed a method for imaging living neuron precursors migrating through explants of embryonic mouse gut. In the current proposal we will meld imaging and genetic studies to understand how mutations in particular genes lead to migration defects. In particular, how do particular mutations affect the migratory behaviour of enteric neural precursors? We have also previously shown that neuron precursors migrate along the gut in close association with axons. We will examine the nature of these interactions - in particular, who is following whom, and what happens when cell migration and axon growth are uncoupled? These studies, which will investigate a number of critical aspects of the migration of neural precursors into and along the developing gut, are central to understanding how the enteric nervous system is established along the gastrointestinal tract.Read moreRead less
Characterisation Of Novel CDKL5 Targets: Implications For Rett Syndrome And Related Neurodevelopmental Disorders.
Funder
National Health and Medical Research Council
Funding Amount
$421,977.00
Summary
Rett syndrome (RTT) is the second most common cause of severe mental retardation in girls and women. Although two genes (MECP2 and CDKL5) responsible for RTT have been identified, we still do not understand how these genes affect brain function. The focus of this research project is to identify which proteins are controlled by CDKL5, with the express hope that a better understanding of these processes will allow us to design specfic therapies for this untreatable devasting disorder.
The Effect Of Very Premature Birth On Brain Development
Funder
National Health and Medical Research Council
Funding Amount
$517,975.00
Summary
The neurological outcome of the premature infant is of major importance. Approximately 2,600 premature infants weighing less than 1500 grams are born annually in Australasia. Of the approximate 2,400 survivors between 5-15% will have a more major cerebral palsy, i.e. around 200 children per annum. A greater proportion of 25-50%, i.e., upto 1200 children will have a developmental disability that will adversely affect their school perfomance requiring special assistance or repeating grades. With a ....The neurological outcome of the premature infant is of major importance. Approximately 2,600 premature infants weighing less than 1500 grams are born annually in Australasia. Of the approximate 2,400 survivors between 5-15% will have a more major cerebral palsy, i.e. around 200 children per annum. A greater proportion of 25-50%, i.e., upto 1200 children will have a developmental disability that will adversely affect their school perfomance requiring special assistance or repeating grades. With an increasing number of very prematurely born infants surviving, the absolute number of affected children will continue to rise. Prevention of these disabilities will require an understanding of the cause. The educational and social implications of these high rates of neuro-developmental disability are enormous and the focus of wide international concern. Magnetic Resonance Imaging : It is a major challenge for neonatologists to be able to understand the impact of their therapies and managements on the developing brain. A window into the newborn brain can be seen utilising advanced magnetic resonance imaging techniques in-vivo to investigate these key issues: 1. What is the nature of brain injury in the prematurely born infant? 2. What are the risk factors for brain injury in the prematurely born infant - and are they able to be altered to reduce this risk - e.g. blood pressure management, steroid therapy 3. Is the brain of a prematurely born infant different from that of a full term born infant at TERM equivalent - if so, how is it different? 4. Are there certain postnatal therapies that relate to any alteration in brain structure and chemistry - e.g. postnatal nutrition, modes of ventilation, pharmacological therapies? 5. How does the brain structure relate to function on long term neuro-developmental follow up of our infants at 2 years?Read moreRead less
Improving The Outcome Of Premature Infants- A Randomised Trial Of Preventive Care At Home
Funder
National Health and Medical Research Council
Funding Amount
$633,375.00
Summary
The high rate of adverse neurodevelopmental outcomes of very premature infants is of major concern. In Australia there are approximately 2600 very low birthweight (VLBW, birthweight <1500 g) or very premature (<30 weeks' gestational age) survivors per annum. A large proportion of these infants (40%-50%) will later develop motor incoordination, cognitive impairment, attention deficits or behavioural problems (up to 1300 new cases per year). There is little research to test the efficacy of e ....The high rate of adverse neurodevelopmental outcomes of very premature infants is of major concern. In Australia there are approximately 2600 very low birthweight (VLBW, birthweight <1500 g) or very premature (<30 weeks' gestational age) survivors per annum. A large proportion of these infants (40%-50%) will later develop motor incoordination, cognitive impairment, attention deficits or behavioural problems (up to 1300 new cases per year). There is little research to test the efficacy of early preventive care programs geared to changing the infant's environment (physical management, behavioural regulation, maternal factors). In the proposed study we aim to use a low cost preventive care program at home conducted by physiotherapists and psychologists that has been shown to have utility and efficacy in pilot work, with follow up until 2 years of age. In subsequent studies we would aim to follow this cohort to school age, to determine if there are any lasting benefits of early intervention accompanied by measures of brain growth and structural development using advanced imaging techniques. Any new health care program should result not only in improvements in health, but should be affordable to implement so an economic evaluation will also be undertaken. This study will also utilise novel and advanced MRI brain imaging techniques to understand the complex interaction between brain injury and altered brain development in these infants with the risk and the repsonse to this program of care. In this way the changes in brain connectivity, structure and biochemistry can be formally defined to undertsnad the pathway of any potential benefit from this program.Read moreRead less
Targeting The Immune Cells Of The Brain To Develop Novel Treatments For Neurodevelopmental And Mental Health Problems In Children
Funder
National Health and Medical Research Council
Funding Amount
$1,800,000.00
Summary
Neurodevelopmental and mental health problems are common in children and cause major impairment and cost to society. This research will define how the maternal immune system while pregnant can affect the baby brain. Using patient studies and laboratory research, this research will result in novel ways to reduce the prevalence and severity of developmental and mental health problems in children and adults, by targeting the immune cells resident in the brain.
Creating A Phenotypic Catalogue Of Synaptic Vesicle Cycling Disorders
Funder
National Health and Medical Research Council
Funding Amount
$876,975.00
Summary
Developmental disorders affect 2-5% of children. In order to understand how these mutations will likely affect neurological function in these individuals, and to develop a tailored care and treatment program, we must first understand how these mutations affect neuronal communication. This research program will identify the underlying cause of neurological dysfunction in a subset of these disorders (synaptic vesicle cycle disorders), affecting 1200-3000 children in Australia alone.
Precision Epigenetics: Targeting The Epigenome To Treat Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,940,576.00
Summary
Epigenetic marks are changes made to the DNA that allow genes to be switched off in some cells and switched on in others. These marks are critical to normal development and often go wrong in disease. We aim to find genes that add epigenetic marks to the DNA and understand how they co-operate at the molecular level to switch genes off. Our focus is on one such gene, SMCHD1. We are developing new drugs against SMCHD1 to treat incurable neurodevelopmental disorder PWS and muscular dystrophy FSHD.