The Role And Underlying Mechanisms Of Constitutional Epigenetic Silencing In Cancer Predisposition
Funder
National Health and Medical Research Council
Funding Amount
$218,617.00
Summary
Familial and young onset bowel and uterine cancer are usually caused by the inheritance of spelling mistakes in the genetic code within a set of cancer-protection genes. Recently, some patients were identified with their gene switched off by paralysing chemicals instead. This study aims to identify additional cancer cases with gene paralysis, determine if this arises in the presence or absence of a genetic change in front of the gene, and how gene paralysis is transmitted to the next generation.
The Role And Inheritance Of Constitutional Epimutations In Early-onset Colorectal Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$347,551.00
Summary
Traditionally familial cancers are thought to be caused by spelling mistakes within the genetic code of cancer prevention genes. Our group has found that chemical attachments to one gene (MLH1) stops it working, even where there is no spelling mistake, and that those chemical changes can be inherited in families with bowel cancer. We will determine how frequently this type of defect occurs in bowel cancer patients, how and why it arises, and if other cancer genes are similarly affected.
Chromosomes are structures that carry genes in all our cells. Every human cell has 46 chromosomes. In the nucleus of eukaryotic cells, DNA is highly folded and compacted with specific proteins into a dynamic polymer called chromatin. Gene expression, chromosome division, DNA replication, and repair all act, not on DNA alone, but on this chromatin template. The discovery that enzymes can (re)organise chromatin into accessible and inaccessible configurations revealed mechanisms that considerably e ....Chromosomes are structures that carry genes in all our cells. Every human cell has 46 chromosomes. In the nucleus of eukaryotic cells, DNA is highly folded and compacted with specific proteins into a dynamic polymer called chromatin. Gene expression, chromosome division, DNA replication, and repair all act, not on DNA alone, but on this chromatin template. The discovery that enzymes can (re)organise chromatin into accessible and inaccessible configurations revealed mechanisms that considerably extend the information potential of the genetic code. In addition, it is now established that chromatin structural features can influence gene expression. In vitro studies support a model in which chromatin functions as a barrier for the access to DNA. Therefore this organization has to be tighly regulated and dynamic to allow the protein-DNA interactions critical for nuclear functions. Importantly genome organisation provides in addition to genetic information another layer of information, so called epigenetic, which by definition means that it is stably inherited throughout cellular divisions, yet it is not encoded genetically. Thus each cell type will display a specific epigenome. We have recently constructed small human minichromosomes, which are much easier to study than the much larger normal chromosomes. The present project proposes to define the epigenetic feature across an entire human chromosome using our minichhromosomes as working models. The outcome will be a significant gain in our knowledge on the processes underlying epigenetic regulation, the organisation of specialised chromatin domain, and behaviour of the chromosomes.Read moreRead less
Adaptive Evolution of BRCA1 in Ancestral Mammals. This project investigates adaptive evolution of BRCA1 in the early radiation of mammals. We will test the hypothesis that the evolution of mammary glands and X chromosome inactivation has resulted in modification of the BRCA1 protein sequence as it aquired new roles in these processes. We will also investigate the importance of these changes inducing compensatory changes in other parts of the protein.
Discovery of novel microRNA biogenesis and functional components. Discovery of novel microRNA components will provide new strategies for confronting a diverse array of challenges Australia faces, such as the increasing rates of certain cancers in our population, to stresses on our crop plants faced with environmental changes. The biological mechanisms underlying these disparate problems are unified by microRNA involvement in many instances. By finding microRNA controlling factors common to all h ....Discovery of novel microRNA biogenesis and functional components. Discovery of novel microRNA components will provide new strategies for confronting a diverse array of challenges Australia faces, such as the increasing rates of certain cancers in our population, to stresses on our crop plants faced with environmental changes. The biological mechanisms underlying these disparate problems are unified by microRNA involvement in many instances. By finding microRNA controlling factors common to all higher organisms, we expect our community will benefit from the increased knowledge base that will help our researchers adopt new strategies in fighting diseases and improving our agricultural industry.Read moreRead less
Identifying potential barriers to transplanting modified forms of the CO2-fixing enzyme, Rubisco, into plants. Improving the ability of crops to use water, light and fertiliser more efficiently would have economic benefits and ease the environmental impacts associated with agricultural practices. It is thought that such improvements can be made by enhancing the efficiency of the photosynthetic protein, Rubisco, which fixes most of the CO2 in the biosphere. The research proposed here uses unique ....Identifying potential barriers to transplanting modified forms of the CO2-fixing enzyme, Rubisco, into plants. Improving the ability of crops to use water, light and fertiliser more efficiently would have economic benefits and ease the environmental impacts associated with agricultural practices. It is thought that such improvements can be made by enhancing the efficiency of the photosynthetic protein, Rubisco, which fixes most of the CO2 in the biosphere. The research proposed here uses unique Rubisco transplantation capabilities that I have developed to improve our fundamental understanding of how Rubisco is processed and its activity regulated in plants. This will pave the way for our ongoing efforts to engineer and transplant more efficient Rubisco into crops.Read moreRead less
Discovering mechanisms of primary embryonic tissue migration through live cell imaging and novel genetic approaches. The studies proposed here will provide concepts and knowledge about the molecular basis of cell migration that will impact on diverse aspects of human health, such as the causes and nature of tumour metastasis and our understanding of the developmental basis of birth defects. In addition, understanding cell migration mechanisms will allow us to better predict or control the behav ....Discovering mechanisms of primary embryonic tissue migration through live cell imaging and novel genetic approaches. The studies proposed here will provide concepts and knowledge about the molecular basis of cell migration that will impact on diverse aspects of human health, such as the causes and nature of tumour metastasis and our understanding of the developmental basis of birth defects. In addition, understanding cell migration mechanisms will allow us to better predict or control the behaviour of therapeutic stem cells introduced into the body.Read moreRead less
The Role Of Duffy And PF4 In The Platelet Killing Of Malaria Parasites.
Funder
National Health and Medical Research Council
Funding Amount
$350,045.00
Summary
Platelets in the blood can kill the Plasmodium parasite, which lives inside red blood cells and causes malaria. Platelets bind parasite-infected red cells and release a molecule that is toxic to the parasite. This project will study why a red cell molecule called Duffy is also needed for this function of platelets. Most Africans carry a gene for Duffy that stops its expression in red cells, and may therefore be more susceptible to malaria because their platelets cannot kill the malaria parasite.
Can efficient algal variants of the photosynthetic CO2-fixing enzyme, Rubisco, be folded and assembled in functional forms in higher-plant plastids? We have shown that it is possible to alter the photosynthetic phenotype of a plant predictably and profoundly by engineering the plastid genome to replace the plant's CO2-fixing enzyme, Rubisco, with a bacterial homolog. Thus it may be possible to replace the plant enzyme with more efficient algal Rubiscos that would allow plants to grow with less l ....Can efficient algal variants of the photosynthetic CO2-fixing enzyme, Rubisco, be folded and assembled in functional forms in higher-plant plastids? We have shown that it is possible to alter the photosynthetic phenotype of a plant predictably and profoundly by engineering the plastid genome to replace the plant's CO2-fixing enzyme, Rubisco, with a bacterial homolog. Thus it may be possible to replace the plant enzyme with more efficient algal Rubiscos that would allow plants to grow with less light, less water or less fertiliser. Before such desirable changes to the plant phenotype can be realised, some complex issues of modification, folding and assembly of Rubisco subunits need to be resolved. This proposal addresses them.Read moreRead less