The Integration Of High Level Clinical Medicine, Molecular Genics, And Cutting Edge Neuroimaging
Funder
National Health and Medical Research Council
Funding Amount
$4,000,000.00
Summary
I aim to cement my place as the leading clinical and translational researcher in epilepsy internationally. My research and that of my wider group is focused on the integration of high level clinical medicine, molecular genetics and cutting-edge neuroimaging, which is informed and enhanced by clinically relevant basic neuroscience. This integrative model is unique in the epilepsy field. The Fellowship will give me the opportunity to expand this model and optimally utilize the rapidly developing t ....I aim to cement my place as the leading clinical and translational researcher in epilepsy internationally. My research and that of my wider group is focused on the integration of high level clinical medicine, molecular genetics and cutting-edge neuroimaging, which is informed and enhanced by clinically relevant basic neuroscience. This integrative model is unique in the epilepsy field. The Fellowship will give me the opportunity to expand this model and optimally utilize the rapidly developing technologies in genetics and imaging which are the two most important and productive fields in clinical neuroscience. I am in a unique international position to do this because of the clinical cohorts that I have meticulously collected and characterized over the last two decades, working with the remarkable group of clinical and basic science investigators that form my personal research team, and the wider group that I head, supported by an NHMRC Program Grant. This Fellowship will provide for a major injection of additional core genetic expertise to take us up to the next level necessary to crack the challenging problem of the complex genetics of the epilepsies. I wish to increase the impact and reputation of my wider group as the International Centre for innovative and clinically relevant research in epilepsy. This will enhance the reputation of Australia as a place of excellence in health and medical research.Read moreRead less
Novel Statistical Methods For Genetic Epidemiology
Funder
National Health and Medical Research Council
Funding Amount
$481,505.00
Summary
We are in the midst of a genomics revolution that is transforming epidemiology, medicine and drug discovery. However, the scarcity of sophisticated statistical techniques to deal with the complicated problems inherent in genetic investigations of complex diseases is currently the critical factor limiting the success of human gene discovery programs. Statistical genetic methodology is currently one of the fastest developing areas of epidemiology. In information-intensive' areas such as genetic ep ....We are in the midst of a genomics revolution that is transforming epidemiology, medicine and drug discovery. However, the scarcity of sophisticated statistical techniques to deal with the complicated problems inherent in genetic investigations of complex diseases is currently the critical factor limiting the success of human gene discovery programs. Statistical genetic methodology is currently one of the fastest developing areas of epidemiology. In information-intensive' areas such as genetic epidemiology, genomics, and proteomics, there is a high demand for data analysis and statistical skills. WA has some world class expertise in statistical science, both in academia and in industry. However, this expertise has not yet been applied in a system way to genetic data analysis. We propose to undertake advanced methodological research in statistical genetics and bioinformatics, to produce easy-to-use and accessible software tools and resources that allow methodological advances to be accessed by the Australian research community, and to apply our new methods and tools both to specific disease research and to the developing human genome epidemiology (HuGE) enterprise in WA. These new initiatives in methodological research will draw together a number of currently separate research strands and will provide new tools and resources that will allow applied Australian programs to improve the efficiency of their research into the causes of important. Methodological development in both bioinformatics and statistical genetics are recognized international areas of need.Read moreRead less
Variation And Inheritance Of Retrotransposon Epigenotype In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$355,500.00
Summary
It is often assumed that traits in humans and other mammals are a product primarily of information encoded in the sequence of DNA, with some contribution from the environment. However, there is clear evidence that traits may vary widely between individuals with precisely the same DNA, such as identical twins, even in circumstances where environmental differences are negligible. This variation can be produced by epigenetic factors chemical changes or protein binding to DNA that alter the way gene ....It is often assumed that traits in humans and other mammals are a product primarily of information encoded in the sequence of DNA, with some contribution from the environment. However, there is clear evidence that traits may vary widely between individuals with precisely the same DNA, such as identical twins, even in circumstances where environmental differences are negligible. This variation can be produced by epigenetic factors chemical changes or protein binding to DNA that alter the way genes are used. Epigenetic factors can be passed from one generation to the next like the DNA itself, and this can make it difficult to know if a trait is encoded in the DNA itself or is epigenetic. We have found that some epigenetic traits in mice are caused by retrotransposons, which are parasitic elements that reside in and among genes, and can reproduce themselves, but do not have any known function (nearly half the human genome is made up of retrotransposons). Retrotransposons are generally kept silent by epigenetic factors, but may sometimes become active; when they do they may disturb normal patterns of gene activity and cause changes in traits and even disease. Much variation in humans may thus be due to variation in the epigenetic state (epigenotype) of retrotransposons. We propose to investigate variation and inheritance of epigenotype in mice, focussing on retrotransposons. We will use simple methods to compare epigenotype of a number of retrotransposons in genetically identical mice, and we will ask if any differences we find are heritable. We will also investigate the resetting of epigenotype the point in development when epigenetic factors are cleared and reset. We suspect that this occurs in early development. These studies may reveal a system of variation and inheritance with rules completely different from those found by Mendel, which may have a pervasive influence on traits, including sporadic diseases in humans.Read moreRead less
A Genome Wide Association Study For Endometriosis Susceptibility Genes
Funder
National Health and Medical Research Council
Funding Amount
$946,750.00
Summary
Endometriosis is a common condition that affects up to 10% of women. Symptoms are severe pelvic pain, menstrual problems and infertility with major impacts on women's lives and relationships. Since 1996, 4,000 affected women plus their families have joined our genetic study. Our aim is to conduct a genome wide search to identify genes contributing to endometriosis. This knowledge will ultimately lead to better diagnosis and treatment for the millions of women who suffer the disease.
The Role Of Proteases In Deafness; Generation Of A Knockout Mouse For Tmprss3 As A Model Of Autosomal Recessive Deafness
Funder
National Health and Medical Research Council
Funding Amount
$70,880.00
Summary
Age-related hearing loss is the most common type of human hearing impairment, affecting approximately half the population by the age of 80. The interaction of predisposing genetic factors with environmental factors is responsible for most age-related hearing loss. Genes underlying genetically inherited hearing impairment also affect susceptibility to age-related hearing loss. Approximately 1-1000 children are born deaf and ~50% of these cases have a genetic cause. Autosomal recessively-inherited ....Age-related hearing loss is the most common type of human hearing impairment, affecting approximately half the population by the age of 80. The interaction of predisposing genetic factors with environmental factors is responsible for most age-related hearing loss. Genes underlying genetically inherited hearing impairment also affect susceptibility to age-related hearing loss. Approximately 1-1000 children are born deaf and ~50% of these cases have a genetic cause. Autosomal recessively-inherited defects are responsible for most cases of genetic deafness (70%) and patients have no other medical problems, indicating that only the inner ear is affected. Genes previously identified for genetic forms of deafness can be broadly classified as either ion channels (e.g. connexins) or structural proteins (e.g. myosins and collagens). We recently identified a novel gene, a transmembrane serine protease, TMPRSS3, which is mutated both in familial and sporadic cases of deafness. Different classes of mutations may cause either deafness from birth or childhood onset deafness. Thus, reduced expression or abnormal function of TMPRSS3 may be involved in age-related hearing loss. This discovery was the first description of a protease involved in hearing loss and the first gene family involved in congenital deafness for which a ready hypothesis for involvement in age-related hearing loss can be made. We will generate and characterize a mouse model to investigate the role of TMPRSS3 in inner ear function and development. We will also isolate and characterize additional members of the transmembrane protease gene family to investigate further the role of proteases in both genetic and age-related hearing loss. This may lead to a greater understanding of the function of the auditory system and, eventually, to new therapeutic protocols.Read moreRead less
I am a clinican-scientist and rheumatologist studying genetic determinants of common chronic human musculoskeletal diseases. My research aims are to define for key genes how specific genotypes promote diease phenotypes, using in vitro and in vivo approac
Development And Evaluation Of Statistical Methods And Software For Analysis Of Complex Genetic Disease Data
Funder
National Health and Medical Research Council
Funding Amount
$1,250,371.00
Summary
What are the major factors underpinning complex genetic diseases like diabetes, bipolar disorder or cancer? To answer this question new tools are needed, including software for mining the human genome with interactions between the genome and environment being incorporated. This is our focus. It will form the basis of a superior understanding of the overall process leading to disease and hence better predictions with important ramifications for new treatments and health care planning.
Genome-wide Combined Linkage-association Scan Of Multiply Phenotyped Twin Sibships
Funder
National Health and Medical Research Council
Funding Amount
$1,920,000.00
Summary
We have a large ongoing study of adolescent twins, their siblings and parents who are multiply phenotyped in many domains including melanoma risk factors, serum biochemistry, and cognition. We used our first Medical Genomics grant to obtain a 5cM linkage scan for>500 families and have identified linkage peaks for many different phenotypes. To fine map these it will be most efficient to carry out a genome-wide association scan. We request funds to type a 500k SNP chip on 1000 individuals.
PIPK2A, A Candidate Gene For Schizophrenia: Impact Of DNA Polymorphisms On Gene- And Protein Expression And -function
Funder
National Health and Medical Research Council
Funding Amount
$454,023.00
Summary
Schizophrenia is a devastating mental disorder with severe impact not only on the individual, but also on families and communities. Prevalence of the illness is worldwide about 0.5% for all populations. More than 200,000 Australians suffer from schizophrenia, costing the Australian community nearly $2 billion each year. The causes for schizophrenia are still unclear. There is now agreement that nature (genetic factors) and nurture (environmental influences) play a role in the development of the ....Schizophrenia is a devastating mental disorder with severe impact not only on the individual, but also on families and communities. Prevalence of the illness is worldwide about 0.5% for all populations. More than 200,000 Australians suffer from schizophrenia, costing the Australian community nearly $2 billion each year. The causes for schizophrenia are still unclear. There is now agreement that nature (genetic factors) and nurture (environmental influences) play a role in the development of the disorder. Evidence for genetic factors has been obtained and consistently confirmed by family-, twin-, and adoption studies. After many years of research, evidence for several genes, conferring susceptibility to schizophrenia, has been obtained by gene finding approaches applied to large family samples with multiple affected members. However, these genes have to be considered as candidates until more is known about their impact on brain function resulting in schizophrenic disorders. We have dissected a gene locus on chromosome 10p detected by linkage analysis by several groups including ourselves. We obtained statistical evidence for association of DNA sequence variants in the gene encoding the enzyme phosphatidyl-4-phosphate 5-kinase with schizophrenia. This enzyme is a critical component of the phosphoinositide pathways, which are involved in cell signalling. Our aim is to identify a possible dysfunction in the pathways. We will search for mutations involved in function or dysfunction of the enzyme. We will investigate gene- and protein expression and enzyme function in lymphoblast cell cultures and in post mortem brain tissue. Our ultimate goal is to characterise the possible impairment of intracellular cell signalling and thus identify molecular targets for development of novel and specific pharmacological treatments that have the potential to replace the currently available medication which is symptom-oriented and usually accompanied by severe adverse effects.Read moreRead less
Identification Of Schizophrenia Susceptibility Genes: A Collaborative Project With The University Of Indonesia
Funder
National Health and Medical Research Council
Funding Amount
$546,825.00
Summary
Schizophrenia is present in all populations at a similar incidence. The project aims to identify genetic risk factors in three genomic regions previously detected by us in a genome-scan for genetic linkage in 152 Indonesian families. Colleagues at the University of Indonesia will collect an additional sample of 2000 individuals for replication. This sample will be available for research in Australia. Knowledge of risk factors will aid in diagnosis, prevention, and development of novel therapies.