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The Role Of GRHL-3, A Mammalian Homologue Of Drosophila Grainyhead, In Neural Tube Development
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Spina bifida and anencephaly are two common human congenital malformations that form part of a wide spectrum of mutations known collectively as neural tube defects (NTDs). Patients with the most severe form of spina bifida have a failure of the vertebral column and skin to close over the spinal cord and therefore suffer from limb paralysis and marked bladder and bowel dysfunction. Infants with anencephaly have an open cranial vault and failure of normal brain development and die within the first ....Spina bifida and anencephaly are two common human congenital malformations that form part of a wide spectrum of mutations known collectively as neural tube defects (NTDs). Patients with the most severe form of spina bifida have a failure of the vertebral column and skin to close over the spinal cord and therefore suffer from limb paralysis and marked bladder and bowel dysfunction. Infants with anencephaly have an open cranial vault and failure of normal brain development and die within the first few hours of life. These abnormalities occur frequently (1-1000 live births) and are a direct result of failure of the neural tube to close during embryogenesis. NTDs are influenced by both environmental and genetic factors. The best characterised environmental factor is the dietary supplement folate, which when administered before conception results in a reduction in the incidence of spina bifida. The genetic complexity is evidenced by the array of mouse genetic mutations that give rise to NTDs. One of these mouse mutations, known as Curly tail (ct), has served as the major animal model of human NTDs. This is because the ct mice are resistant to folate administration (like most of the cases of spina bifida currently seen in patients) and because the mice seem to have normal development in virtually all other organ systems. Ironically, the genetic mutation that causes the curly tail phenotype has remained undiscovered for over 50 years. We have now identified the gene mutated in the curly tail mice. This gene is highly conserved in humans suggesting that it will play a similar role in neural tube development in man. The gene, known as GRHL-3, is a descendant of a fly gene critical for development of the nervous system in that organism. The studies we propose here will examine the developmental pathways involved in normal neural tube closure in mice and humans and will impact on our understanding of these devastating congenital malformations.Read moreRead less
Mechanisms Of Premature Cranial Fusion: Role Of Retinol Binding Protein 4 In Osteogenesis And Suture Fusion
Funder
National Health and Medical Research Council
Funding Amount
$555,855.00
Summary
Craniosynostosis is a condition where the skull bones fuse prematurely, affecting skull shape, vision and cognition. It occurs in 1 in 2,500 births. The only treatment is surgery, which is life-threatening, costly and may need to be repeated. By studying how fusion happens in this project we may be able to devise therapies to minimize the risks and need for re-operation. Here, we hope to show that modification of a single substance in the skull of mouse models can prevent premature bone fusion.
GENETIC PREDICTION OF FRACTURE IN A RISK-STRATIFIED POPULATION
Funder
National Health and Medical Research Council
Funding Amount
$363,000.00
Summary
Osteoporosis is a condition characterised by excessive bone loss and impaired bone quality, which ultimately results in fracture with minimal trauma. Osteoporosis affects 27% of women and 11% of men aged 60 years or above in the community, and costs Australia around $7 billion each year. Individuals with low bone mineral density (BMD) have a significantly higher risk of fracture than those with normal BMD. In the long-term (14-year) Dubbo Osteoporosis Epidemiology Study, more than half of indivi ....Osteoporosis is a condition characterised by excessive bone loss and impaired bone quality, which ultimately results in fracture with minimal trauma. Osteoporosis affects 27% of women and 11% of men aged 60 years or above in the community, and costs Australia around $7 billion each year. Individuals with low bone mineral density (BMD) have a significantly higher risk of fracture than those with normal BMD. In the long-term (14-year) Dubbo Osteoporosis Epidemiology Study, more than half of individuals with osteoporosis (e.g., low BMD) did not sustain a fracture, while approximately 60% of fracture cases had BMD above the high risk levels. Thus, BMD alone is not a good discriminant of fracture versus non-fracture cases. It is widely known that the liability to fracture is determined in part by genes. Previous studies, including from our group, have suggested a number of candidate genes that are associated with fracture risk. The fundamental issue that this study is concerned is that how and whether genetic markers could be used to facilitate case finding. It is proposed that common variations of certain genes are associated with fracture risk independent of BMD. That is, they can identify individuals at relatively high and low fracture risk after stratification for BMD. Hence, some markers may identify those individuals likely (and unlikely) to fracture even with low (osteoporotic) BMD. Similarly, some, possibly the same, markers may identify individuals at high risk of fracture despite relatively good (ie non-osteoporotic) BMD. It is further proposed that no single gene will achieve this outcome, but rather a small set of such gene polymorphisms will provide clinically useful risk information. This effect is entirely analogous to the use of clinical risk indicators (eg, age, weight, sex, family history, etc) to assess the risk of future fracture.Read moreRead less
Many new therapies are being developed to treat stroke and prevent its recurrence. While a number of these have been successfully introduced, there is a puzzling gap between evidence of efficacy in animal models and humans. One of the main reasons may be lack of an integrated approach between the basic sciences and clinical researchers. By assembling a team with skills in both areas and a structure to maximise communication between groups this team plan to incrementally introduce new therapies i ....Many new therapies are being developed to treat stroke and prevent its recurrence. While a number of these have been successfully introduced, there is a puzzling gap between evidence of efficacy in animal models and humans. One of the main reasons may be lack of an integrated approach between the basic sciences and clinical researchers. By assembling a team with skills in both areas and a structure to maximise communication between groups this team plan to incrementally introduce new therapies into clinical practice.Read moreRead less
How Do Bone-active Drugs Increase Patient Survival?
Funder
National Health and Medical Research Council
Funding Amount
$613,952.00
Summary
Bisphosphonates are a class of drugs used to prevent bone destruction in diseases such as osteoporosis. Evidence is emerging that these drugs also act on cells outside the skeleton to have additional beneficial effects, for example prolonging patient survival. This project will identify the cells affected and the mechanisms involved. With this knowledge, these drugs could be used more effectively and in different ways for the prevention or treatment of cancer and chronic human illnesses.
I am a cancer cell biologist investigating molecular mechanisms of leukaemia cell resistance to chemotherapeutic drugs, and novel strategies for the management of high risk or relapsed disease. For these purposes I have developed orthotopic xenograft mode
THE EFFECTS OF TRANSCRANIAL MAGNETIC STIMULATION (TMS) ON RAT MODELS OF DEPRESSION
Funder
National Health and Medical Research Council
Funding Amount
$204,274.00
Summary
Repetitive Transcranial Magnetic Stimulation (rTMS) is the direct stimulation of the brain by using high field magnetic pulses. It is a new technique that has been demonstrated to have some potential as a treatment of depressive illness and possibly other neuropsychiatric disorders. At this early stage of its investigation, the parameters of stimulation that are most likely to be therapeutic, and its mechanisms of action, are not known. Published studies vary in the frequency, duration and exten ....Repetitive Transcranial Magnetic Stimulation (rTMS) is the direct stimulation of the brain by using high field magnetic pulses. It is a new technique that has been demonstrated to have some potential as a treatment of depressive illness and possibly other neuropsychiatric disorders. At this early stage of its investigation, the parameters of stimulation that are most likely to be therapeutic, and its mechanisms of action, are not known. Published studies vary in the frequency, duration and extent of stimulation, with no firm guidelines about optimal parameters. Empirical study of the relative effects of stimulation at different frequencies, at different numbers of stimuli and for different durations is therefore important for the future development of this treatment. Such an investigation is best carried out in an animal model of depression for both ethical and practical reasons, as such studies in patients would possibly take many years and be extremely difficult to conduct. We propose such a study in rat models of depression which have demonstrated validity and utility in drug research. Rat models have a long track record in developing psychiatric treatments and are cost-effective and of proven value. We also plan to investigate the neuroanatomy of the immediate-early genes induced by TMS and compare it with electroconvulsive shock (ECS) and a tricyclic antidepressant, two established treatments of depression. The results will have implications for future human studies in guiding us toward the optimal parameters for therapeutic effects. They will also enhance our understanding of the mechanism of action of TMS in depression.Read moreRead less
Inflammatory skin disorders, such as psoriasis and dermatitis, are responsible for a large burden of human disease and affect people across alldemographics. Knockout (KO) of TNF signalling members in mice is known to induce skin inflammation. This project proposes to use these genetic mouse models to investigate how and why disruption of particular TNF superfamily members leads to disease and potentially identify new targets for treatment.
Determination Of Irradiation Dose Efficacy For Use In Impaction Grafting At Revision Joint Replacement
Funder
National Health and Medical Research Council
Funding Amount
$411,517.00
Summary
Primary hip replacement is a successful intervention for hip disease, but 10-15% of hip prostheses fail and require revision surgery within 10-15 years. At the time of revision, significant bone loss around the failed prosthesis is not uncommon. A bone reconstruction procedure, called impaction grafting, where donor bone is minced and placed in the areas of deficient bone before implanting the new prosthesis, has shown to give good results at more than ten years in some centres. A high incidence ....Primary hip replacement is a successful intervention for hip disease, but 10-15% of hip prostheses fail and require revision surgery within 10-15 years. At the time of revision, significant bone loss around the failed prosthesis is not uncommon. A bone reconstruction procedure, called impaction grafting, where donor bone is minced and placed in the areas of deficient bone before implanting the new prosthesis, has shown to give good results at more than ten years in some centres. A high incidence of early complications of this procedure have included loss of fixation within the bone. Fracture of the bone around prostheses has also reported in some centres. These events require more surgery, putting the patient at higher risk greater complications and longer rehabilitations. Recent improvements in surgical technique and donor bone preparation have improved results. A current debate questions whether the dose of irradiation can be reduced from 25 kGy, while maintaining sterility of allografts. The risk of bacterial contamination in allografts is low, and irradiation reduces the mechanical strength of the graft, contributing to complications when irradiated bone is used. The benefits of decontaminating the bone may be outweighed by the higher risk for failure due to poor bone quality and resulting prosthesis instability. We will use ISO standards to test the validity of radiation dose for sterilising bone ex vivo. In the absence of controlled human studies, our aim is also to compare the results of impaction grafting with non-irradiated bone versus bone irradiated at current doses used by Australian bone banks, and lower doses indicated by ex vivo testing. We will use a large animal model of revision hip replacement, with precise measures of prosthesis stability. The results of this study will guide clinical decisions regarding the efficacy of current bone graft preparation procedures and the use of irradiated bone in human hip replacement surgery.Read moreRead less
Tyrosine Kinase Receptor C-ros-oncogene 1 Mediates Twist-1 Haploinsufficiency Induced Craniosynostosis In Children: A Novel Therapeutic Target
Funder
National Health and Medical Research Council
Funding Amount
$562,863.00
Summary
Children with Saethre-Chotzen syndrome exhibit premature fussed coronal sutures, and other skull/ skeletal malformations. Surgical intervention is the only treatment option to ensure optimal cognitive and skeletal development. Our studies have identified a candidate molecular pathway that regulates bone formation by cranial bone cells from these patients. Targeting these key molecular signalling components with chemical inhibitors will help prevent the premature fusion of cranial sutures.