Molecular Identification Of Causative Genetic And Epigenetic Alterations That Induce And Promote Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$381,821.00
Summary
The majority of mouse models currently employed to study colorectal cancer have two failings. The first is that they tend to focus on small intestinal cancers rather than colorectal cancers. It is important to note that small intestinal cancers are in the minority of gastrointestinal cancers in humans. The second problem is that the genetic lesions introduced into mice are mostly in all cells throughout development. This is a poor representation of the random nature of genetic changes that under ....The majority of mouse models currently employed to study colorectal cancer have two failings. The first is that they tend to focus on small intestinal cancers rather than colorectal cancers. It is important to note that small intestinal cancers are in the minority of gastrointestinal cancers in humans. The second problem is that the genetic lesions introduced into mice are mostly in all cells throughout development. This is a poor representation of the random nature of genetic changes that underpin the probable cause of colon cancer. We therefore propose to genetically engineer unique mouse models that focus on colon cancer to most closely replicate the situation in human disease. These models will then be available to others and us to develop and test therapies to prevent and-or treat colorectal cancer that will ultimately be used in patients.Read moreRead less
The Role Of Nutrition In Disease-linked Epigenetic Inheritance
Funder
National Health and Medical Research Council
Funding Amount
$485,412.00
Summary
This project aims to investigate one mechanism behind fetal programming, in which a suboptimal in utero environment can affect health of offspring in later life. We and others have recently shown that fetal programming can be caused by changes in the way genes behave, and we will examine how many genes are affected by these changes. We will ask whether the changes can increase in frequency with long-term exposure to nutritional stress, and become entrenched within the population.
Role Of DNA Methylation And Non-coding RNA In Human Centromere Function
Funder
National Health and Medical Research Council
Funding Amount
$499,000.00
Summary
A chromosome is a grouping of coiled strands of DNA, containing many genes. Every human cell has 23 pairs of chromosomes, which together comprise the genome. Both gain and loss of any of these chromosomes will lead to severe medical problems including birth defects and cancer development. Thus, the understanding of the mechanisms underlying the exact passage of these chromosomes from a parental cell to two new cells during cell division, and how the information is copied from from one cell gener ....A chromosome is a grouping of coiled strands of DNA, containing many genes. Every human cell has 23 pairs of chromosomes, which together comprise the genome. Both gain and loss of any of these chromosomes will lead to severe medical problems including birth defects and cancer development. Thus, the understanding of the mechanisms underlying the exact passage of these chromosomes from a parental cell to two new cells during cell division, and how the information is copied from from one cell generation to another, is an important area of research, however, much remains to be learnt about the mechanisms. Our laboratory was the first to discover a key component of the chromosome that is involved in the regulation of the cell division process, ensuring the accurate segregation of chromosomes. This structure, known as a neocentromere, is an ideal model system to study important aspects of chromosome segregation. The present project proposes to study the properties of this neocentromere in detail. The outcome will contribute to our knowledge on the processes underlying cell and chromosome division, which will ultimately have a direct impact on our understanding of the causes for some of the most common clinical conditions that affect human health.Read moreRead less
Variable Expressivity And Epigenetic Inheritance At The Axin Fused Locus In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
Genes influence the way we look and variations in gene sequence can account for the differences between individuals. Family traits are often credited to gene variants that are passed down through generations of families. There is now intriguing evidence, some coming from our laboratory, that gene sequence is not the only thing we inherit from our parents. Modifications that alter the expression but not the sequence of a gene, known as epigenetic modifications can, it turns out, be inherited in m ....Genes influence the way we look and variations in gene sequence can account for the differences between individuals. Family traits are often credited to gene variants that are passed down through generations of families. There is now intriguing evidence, some coming from our laboratory, that gene sequence is not the only thing we inherit from our parents. Modifications that alter the expression but not the sequence of a gene, known as epigenetic modifications can, it turns out, be inherited in mammals. An epigenetic modification is a mark, present on some genes that determines whether the gene is expressed (switched on) or silent. Animals are thought to acquire this mark during development and it is retained throughout life except in germ cells where the mark is generally, but not always, erased. The establishment of the mark appears to be a stochastic event at the cellular level resulting in mosaic expression. The percentage of marked cells can differ from one individual to another . In theory, this could help to explain why individuals with identical genetic information, such as identical twins, can have different phenotypic characteristics. The fact that these modifications can be inherited implies that there is an alternative mode of inheritance of genetic traits which does not involve mutation but which can be carried from generation to generation in a semipermanent way. Understanding the mechanisms underlying these events is important if we wish to predict or modify the phenotype of an invidual or that of his or her offspring.Read moreRead less
Application Of New Technologies And Methods In Nutrition Research – The Example Of Phenotypic Flexibility
Funder
National Health and Medical Research Council
Funding Amount
$210,823.00
Summary
The aim of the Nutritech project is to develop better diagnostics of the effect of foods and dietary supplements on the health of an individual. NutriTech will develop new analytical technologies to comprehensively investigate the diet-health interrelationship and critically assess their usefulness for the future of nutrition research. A new automated method for measuring the effect of diet on multiple measures of DNA damage and nutrients in single cells will be developed at CSIRO.
Bushfire Smoke Exposure During Pregnancy And Epigenetic Changes In Offspring
Funder
National Health and Medical Research Council
Funding Amount
$1,707,578.00
Summary
The Australian bushfire season of 2019/2020 was unprecedented in terms of length and intensity, and a question of significant importance to public health for the community is whether exposure to bushfire smoke has long term impacts on children whose mothers were pregnant at the time. This grant investigates a potential mechanism called epigenetics (which changes the way genes are expressed in response to environmental conditions), in newborns whose mothers were exposed to bushfire smoke.
Analysis Of The Osteoclast Methylome For Characterisation Of Epigenetic Mechanisms Underlying Metabolic Bone Disease
Funder
National Health and Medical Research Council
Funding Amount
$299,018.00
Summary
A large number of genetic variants have been identified that have a role in osteoporosis, however for many of these, the mechanism by which they influence the disease remains to be determined. This study will fill a critical knowledge gap by investigating the epigenetic control of gene expression in osteoclasts (bone resorbing cells). This research will generate a unique international resource that will provide foundation data to understand and treat this prevalent and debilitating bone disease.
One of the interesting questions in human biology is why monozygotic twins, which have an identical genetic make up, can still vary in many complex traits such as height, eye colour and susceptibility to various mental and disease states. It is clear that this variation is not always due simply to environment. We propose in this application to show that, even if the genetic code is identical in monozygotic twins, epigenetic marks such as DNA methylation and histone modifications can vary between ....One of the interesting questions in human biology is why monozygotic twins, which have an identical genetic make up, can still vary in many complex traits such as height, eye colour and susceptibility to various mental and disease states. It is clear that this variation is not always due simply to environment. We propose in this application to show that, even if the genetic code is identical in monozygotic twins, epigenetic marks such as DNA methylation and histone modifications can vary between critical genes giving rise to differences in gene expression patterns. We propose that the variation in the methylation pattern arises after the two embryos have split, at a time when the developing embryo undergoes genome-wide demethylation followed by de novo re-methylation. The importance of this project is NOT what it tells us about twins themselves, but that twins can provide the clue to disease processes which affect everybody in the population. The results of these experiments will determine the extent to which epigenetic changes to the genome that occur early in embryonic development provide an additional source of variation in gene expression that could contribute to phenotypic variation. By using identical twins we eliminate the possibility that epigenetic modifications that we observe are themselves influenced by genotype. Determining these epigenetic differences will provide an insight into the mechanisms underlying complex traits and human disease.Read moreRead less
In this grant we aim to study the moecular basis of cancer. The promoter regions of tumour suppressor genes are often modified in cancer by a chemical process called methylation. Methylation of DNA is associated with gene silencing. Therefore DNA methylation is commonly regarded as causing the silencing of genes in cancer. In this grant, we aim to determine if methylation is causal in triggering gene silencing in cancer, or if methylation is a consequence of gene silencing. This is a critical di ....In this grant we aim to study the moecular basis of cancer. The promoter regions of tumour suppressor genes are often modified in cancer by a chemical process called methylation. Methylation of DNA is associated with gene silencing. Therefore DNA methylation is commonly regarded as causing the silencing of genes in cancer. In this grant, we aim to determine if methylation is causal in triggering gene silencing in cancer, or if methylation is a consequence of gene silencing. This is a critical distinction in understanding the role of methylation in cancer development.Read moreRead less