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
Modelling The Effects Of Immunity On Influenza Transmission - Implications For Prevention And Vaccine Development
Funder
National Health and Medical Research Council
Funding Amount
$275,767.00
Summary
There is uncertainty about how many people can be infected by a single person with influenza at the start of an outbreak. Some data suggest that a single generation of transmission can infect 10-20 other people. With such a rate of growth (ie 10-20 fold every 3 days) the spread of an influenza outbreak is virtually unstoppable. Other data suggest that each person with influenza infects less than 2 other people on average. With such a lower rate of growth, control would be more feasible. Our proj ....There is uncertainty about how many people can be infected by a single person with influenza at the start of an outbreak. Some data suggest that a single generation of transmission can infect 10-20 other people. With such a rate of growth (ie 10-20 fold every 3 days) the spread of an influenza outbreak is virtually unstoppable. Other data suggest that each person with influenza infects less than 2 other people on average. With such a lower rate of growth, control would be more feasible. Our project will use data from historic and contemporary outbreaks of influenza and build mathematical models to explain the rate of growth of an influenza outbreak in terms of: 1. The proportion of people exposed to influenza who do not become ill (although there can be evidence of infection if careful studies are made). This proportion is about 33%. 2. The proportion of people who are protected from influenza by immunity, whether induced by vaccination or by past exposure to natural influenza infection (this can vary from 0% in isolated populations which have not seen influenza for many years up to 80 or 90% in urbanised populations that are exposed to influenza almost every season). 3. Different rates of contact between different people and groups of people - some may be exposed so often that their immunity is boosted regularly without them becoming severely ill; others, living in more isolated circumstances, may be rarely exposed, but when they are, they are more likely to become severely ill. 4. The effects of influenza vaccine in inducing protective immunity - it is well known that there is good protection if the vaccine is well matched to the circulating virus. 5. The effects of live virus infection in inducing (short-lived) protection against a wider range of influenza viruses. Our model results will be used to guide vaccine design and pandemic planning.Read moreRead less
Novel Approaches For Activation And Expansion Of Genetically Modified T Cells In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$115,660.00
Summary
Killer T lymphocytes can penetrate tumors and their propagation and transfer into cancer patients has demonstrated some encouraging results, but this form of adoptive immunotherapy remains ineffective in most cancer patients. We propose to improve the tumor trafficking and anti-tumor activities of killer cells by genetically engineering them with proteins that will enable them to recognise and destroy cancer cells. Our previous work has indicated that killer T lymphocytes can be genetically engi ....Killer T lymphocytes can penetrate tumors and their propagation and transfer into cancer patients has demonstrated some encouraging results, but this form of adoptive immunotherapy remains ineffective in most cancer patients. We propose to improve the tumor trafficking and anti-tumor activities of killer cells by genetically engineering them with proteins that will enable them to recognise and destroy cancer cells. Our previous work has indicated that killer T lymphocytes can be genetically engineered in culture with tumor recognition receptors. When transferred into mice, these genetically engineered cells can release toxic and inflammatory proteins that cause tumor destruction. In this proposal we wish to further test this approach in mice by enginneering the mouse killer T cells with (i) receptors that provide stronger signals for killing and proliferation; and (ii) with receptors targeting other structures on tumor cells including the tumor vasculature as a means to overcome tumor escape. In addition, we wish to test a novel approach of combining both genetic engineering and vaccination strategies for expanding gene-modified cells after adoptive transfer. These studies will allow the best receptor genes to be transferred to human white blood cells and examined for anti-tumor effects in immune-deficient mice.Read moreRead less