Epigenetic Regulation Of L1 Retrotransposition In Mouse Models Of Abnormal Human Neurobiology
Funder
National Health and Medical Research Council
Funding Amount
$417,812.00
Summary
Retrotransposons are mobile genes that copy-and-paste themselves to spread in DNA. Until very recently, they were thought to only be active in sperm and egg. In our recent work, we demonstrated that they also move in the brain. In the current study, we will use cutting-edge technologies to determine how retrotransposons change the genetic makeup of neurons in neurodevelopmentally impaired mice to predict whether these mutations would also be present in human brain disorders.
Genetic, Family And Social Determinants Of The Burden And Outcome In Rett Syndrome: A Population-based Investigation
Funder
National Health and Medical Research Council
Funding Amount
$332,550.00
Summary
Rett syndrome is a severe disorder of the nervous system mainly affecting females. At birth children with Rett syndrome often seem normal but in their second year lose skills. With time it becomes clear that they are severely intellectually and physically handicapped. In 1999 the link between Rett syndrome and a mutation in the gene, known as MECP2, was found. In Australia since 1993, we have had a register of basic information on all girls and young women diagnosed with Rett syndrome. Over thre ....Rett syndrome is a severe disorder of the nervous system mainly affecting females. At birth children with Rett syndrome often seem normal but in their second year lose skills. With time it becomes clear that they are severely intellectually and physically handicapped. In 1999 the link between Rett syndrome and a mutation in the gene, known as MECP2, was found. In Australia since 1993, we have had a register of basic information on all girls and young women diagnosed with Rett syndrome. Over three quarters of the register s 248 cases have now been genetically tested. In 2000 and again in 2002, extra information on ability to do everyday tasks, behaviour, hand function, medical conditions, and use of health and education services was collected. In 2002 questions on family well being were also included. From 2004 to 2007, further information will be gathered on function, health and well being of the affected child and their family. This will be by telephone interview, questionnaire, video recording, existing medical records, clinical assessments and tests. This will include in 2004 completion of calendars which will provide information needed to estimate health and medical care costs for these children. Similar information by questionnaire and calendar will also be collected from the parents of children with Down syndrome in 2004. The information will be used to compare the social and financial burden of Rett syndrome with Down syndrome, a commoner cause of intellectual disability. The research will also show if it is possible to predict from early genetic test results how severely a child with Rett syndrome will later be affected. It will also determine whether some ways of management improve the long-term outlook for the girl and her family. Finally this study will investigate why some families cope better with this devastating disorder than others. This research is only possible in Australia because of the ongoing register we have set up here.Read moreRead less
Identification Of Variably Expressed Genes In Isogenic Mice And Humans
Funder
National Health and Medical Research Council
Funding Amount
$293,080.00
Summary
Monozygotic twins are known to have different phenotypic characteristics even though they contain identical genetic information. It is not uncommon for identical twins to have different coloured eyes and to show discordance for genetic diseases. While there is no definitive explanation for these differences they are generally thought to be caused by subtle changes in environmental conditions. We believe however, that these differences are set up during early embryonic development by the establis ....Monozygotic twins are known to have different phenotypic characteristics even though they contain identical genetic information. It is not uncommon for identical twins to have different coloured eyes and to show discordance for genetic diseases. While there is no definitive explanation for these differences they are generally thought to be caused by subtle changes in environmental conditions. We believe however, that these differences are set up during early embryonic development by the establishment of epigenetic modifications to the DNA. An epigenetic modification is a mark which determines whether a gene is expressed (switched on) or silent (switched off). The establishment of the mark appears to be a stochastic event which can result in different physical characteristics between genetically identical individuals. We would like to study this process in inbred mouse strains and in humans. Inbred mouse strains are maintained by inbreeding (brother-sister mating) to ensure that all individuals of the strain are isogenic (genetically identical) and in such a way that environmental variation is minimised. We will use established molecular techniques to find genes which are variably expressed among isogenic mice and humans. This work will enable us to discover genes which are sensitive to epigenetic modifications and whose epigenotype must be known if we are able to predict phenotype or disease state.Read moreRead less
Could Pharmacological Restoration Of Mecp2 Levels Be Of Therapeutic Value In Rett Syndrome?
Funder
National Health and Medical Research Council
Summary
Rett syndrome is one of the commonest single gene cause of developmental disability in girls; 1:8500 Australian females are affected by the age of 12. There is currently no cure. Rett syndrome most commonly results from a fault in one copy of the Mecp2 gene on the X chromosome. The proposed research aims to identify medicines, already known to be safe in children and adults, which specifically improve the functioning of the Mecp2 gene. This should rapidly lead to targeted clinical treatments for ....Rett syndrome is one of the commonest single gene cause of developmental disability in girls; 1:8500 Australian females are affected by the age of 12. There is currently no cure. Rett syndrome most commonly results from a fault in one copy of the Mecp2 gene on the X chromosome. The proposed research aims to identify medicines, already known to be safe in children and adults, which specifically improve the functioning of the Mecp2 gene. This should rapidly lead to targeted clinical treatments for this condition.Read moreRead less
A New Paradigm For SWI/SNF Chromatin Function; The ATPase Dependent Remodeler Is A Component Of The MeCP2 Complex
Funder
National Health and Medical Research Council
Funding Amount
$254,250.00
Summary
DNA methylation is a major determinant in the epigenetic silencing of many genes. The mechanisms underlying that targeting of DNA methylation and the consequence, that is, transcriptional silencing are relevant to human development and disease. Examples of the significance of alterations in the controls of DNA methylation and histone deacetylation in human disease include mental retardation (fragile X syndrome, Rett syndrome) and carcinogenesis. Evidence is emerging that a family of methylation ....DNA methylation is a major determinant in the epigenetic silencing of many genes. The mechanisms underlying that targeting of DNA methylation and the consequence, that is, transcriptional silencing are relevant to human development and disease. Examples of the significance of alterations in the controls of DNA methylation and histone deacetylation in human disease include mental retardation (fragile X syndrome, Rett syndrome) and carcinogenesis. Evidence is emerging that a family of methylation specific (methyl-CpG binding domain, MBD) proteins have the capacity to bind to methylated sequences and repress transcription. The mechanisms that target CpG methylation however still remain unclear. Furthermore, it is becoming increasingly evident that methyl-CpG binding proteins are not alone in silencing transcription and other epigenetic components are thought to influence transcription (namely, SWI-SNF activation complex). This grant proposal concentrates on our most recent work which demonstrates a new molecular mechanism of transcriptional repression extending the mechanism mediated by MeCP2. Our results are the first to show that the human SWI-SNF ATPase complex is a transcriptional repressor and is identified as part of the MeCP2-histone deacetylase repressor complex. This data extends the mechanistic link between DNA methylation, chromatin remodelling and transcriptional regulation. More importantly, the experimental findings could lead to a re-examination of the mechanistic basis behind MeCP2 transcriptional repression and epigenetic modification. Our findings suggest a new paradigm for SWI-SNF as a component of the MeCP2 methylation dependent silencing complex.Read moreRead less
Towards Evidence-based Care For Rett Syndrome: A Research Model To Inform Management Of Rare Disorders
Funder
National Health and Medical Research Council
Funding Amount
$458,046.00
Summary
Rett syndrome is a rare but serious genetic neurological disorder affecting mainly girls and often complicated by spinal curvature and poor growth. This project will use national register data collected over 16 years to examine change in functional abilities and progression of the scoliosis curve. It will develop guidelines and improve processes to assist with diagnosis and will comprehensively evaluate the surgical treatments used in the management of scoliosis and growth problems.
The Nutritional Geometry Of Ageing In A Rodent Model
Funder
National Health and Medical Research Council
Funding Amount
$979,269.00
Summary
A central belief in ageing research is that eating fewer calories prolongs life, and that the source of calories (carbohydrate, fat or protein) is irrelevant. However, a critical assessment indicates that this conclusion is premature. We will use recent techniques in nutrition to define for the first time in mammals the relationship between diet and ageing in a normal and a prematurely ageing strain of mice. The project will provide a novel nutritional approach for promoting healthy ageing.