Transcriptional regulation of erythropoiesis. The major expected outcome from this proposal will be development of a pipeline for the study of how transcription factors work at a genome level. There will be national benefit in the areas of Frontier Technologies, and Promoting and Maintaining Good Health. There will be specific outcomes with respect to development of tests for human blood diseases, future design of drugs to target the aberrant activities of transcription factors in genetic and de ....Transcriptional regulation of erythropoiesis. The major expected outcome from this proposal will be development of a pipeline for the study of how transcription factors work at a genome level. There will be national benefit in the areas of Frontier Technologies, and Promoting and Maintaining Good Health. There will be specific outcomes with respect to development of tests for human blood diseases, future design of drugs to target the aberrant activities of transcription factors in genetic and degenerative diseases. Also, a strong bridge will be built upon the previous collaborations of the research teams in Brisbane and Pennsylvania, which will facilitate advanced teaching and training of Australian PhD and post-doctoral scientists.Read moreRead less
microRNAs: discovery and analysis in mouse development. MicroRNAs (miRNAs) are a new class of regulatory molecule, recently found to be abundant and strongly conserved in several eukaryotic species, encoded by genes that are transcribed into short stem-loop structures and then processed into ~22nt single-stranded RNAs by the RNAi pathway. We have cloned novel miRNAs, and obtained the first evidence for regulation of a miRNA in a mammal. We propose to continue cloning novel miRNAs by the tried m ....microRNAs: discovery and analysis in mouse development. MicroRNAs (miRNAs) are a new class of regulatory molecule, recently found to be abundant and strongly conserved in several eukaryotic species, encoded by genes that are transcribed into short stem-loop structures and then processed into ~22nt single-stranded RNAs by the RNAi pathway. We have cloned novel miRNAs, and obtained the first evidence for regulation of a miRNA in a mammal. We propose to continue cloning novel miRNAs by the tried method, and to explore bioinformatics-based methods of identification. We will also study the expression of miRNAs in mouse embryos at successive stages, and develop a microarray assay for miRNA expression.Read moreRead less
Exploration of a mechanistic link between eukaryotic transcription and translation. Gene transcription is functionally coupled to other aspects of eukaryotic mRNA metabolism, emphasizing a need for integrated approaches to analyse the gene expression pathway. We have shown in previous work that yeast cells, when responding to external stimuli, show a tight correlation between changes in the transcriptome composition and homodirectional alterations in the translation state of mRNAs. This phenomen ....Exploration of a mechanistic link between eukaryotic transcription and translation. Gene transcription is functionally coupled to other aspects of eukaryotic mRNA metabolism, emphasizing a need for integrated approaches to analyse the gene expression pathway. We have shown in previous work that yeast cells, when responding to external stimuli, show a tight correlation between changes in the transcriptome composition and homodirectional alterations in the translation state of mRNAs. This phenomenon of ?potentiation? may serve to amplify signal-induced changes in the transcriptome at the translational level. This project will begin to unravel the molecular mechanisms underlying potentiation using experiments designed to distinguish between transcription- and translation-driven mechanisms.Read moreRead less
Identification of Biological pathways regulated by circular RNAs. Circular RNAs (circRNAs) are a, recently discovered molecule. circRNAs are highly abundant and expressed in a tissue and disease specific manner. Yet, currently the understanding of how circRNAs regulate biological processes is very poor. This project aims to use pooled shRNA libraries to screen a large panel of cell lines and systematically identify cellular activities that are regulated by circRNAs. The expected outcome of this ....Identification of Biological pathways regulated by circular RNAs. Circular RNAs (circRNAs) are a, recently discovered molecule. circRNAs are highly abundant and expressed in a tissue and disease specific manner. Yet, currently the understanding of how circRNAs regulate biological processes is very poor. This project aims to use pooled shRNA libraries to screen a large panel of cell lines and systematically identify cellular activities that are regulated by circRNAs. The expected outcome of this study will be a catalogue of functionally active circRNAs. Over the past decades, the wealth of knowledge on the function of linear mRNAs has had a significant impact on medicine and agriculture. Similarly understanding how circRNAs regulate cellular activities may have an analogous impact on humans.Read moreRead less
The role of epigenetics in the early gestational programming of adult phenotype by ethanol. The concept of foetal programming is changing the way we think about the aetiology of complex disease in adults. Our studies would emphasise that adverse events during pregnancy can have long-term health implications, with concomitant social and economic consequences. In America, the prevalence of foetal alcohol syndrome is comparable with rates for Down syndrome. The Aboriginal community in Australia ....The role of epigenetics in the early gestational programming of adult phenotype by ethanol. The concept of foetal programming is changing the way we think about the aetiology of complex disease in adults. Our studies would emphasise that adverse events during pregnancy can have long-term health implications, with concomitant social and economic consequences. In America, the prevalence of foetal alcohol syndrome is comparable with rates for Down syndrome. The Aboriginal community in Australia has been identified as a high-risk group. The knowledge gained from this project could aid in the development of screening strategies to predict the likelihood of disease developing later in life, providing an opportunity for presymptomatic healthcare.Read moreRead less
Does developmental noise have an epigenetic basis? One's ultimate phenotype is the result of a combination of genotype and environment, and includes a poorly understood component termed ?developmental noise?. The molecular basis of developmental noise remains unknown, but it appears to be established in early development and to be retained for the life of the organism. We propose that the molecular basis of developmental noise is the epigenetic state of the genome. The stochastic nature of th ....Does developmental noise have an epigenetic basis? One's ultimate phenotype is the result of a combination of genotype and environment, and includes a poorly understood component termed ?developmental noise?. The molecular basis of developmental noise remains unknown, but it appears to be established in early development and to be retained for the life of the organism. We propose that the molecular basis of developmental noise is the epigenetic state of the genome. The stochastic nature of the establishment of epigenetic state, combined with its heritability during mitosis, provides all the essential components for developmental noise. If our hypothesis proves correct, our work will have a major impact on the understanding of one of the most basic concepts in genetics.Read moreRead less
Novel bioinformatics approaches for biological inference from comparative genomics data. Unlocking the potential of the human and other genome sequences depends almost entirely upon comparative genomics techniques. We will develop powerful bioinformatic models, implemented as high-performance computing solutions, for the examination of gene sequences. Improving these models, which represent the initial building block for all comparative genomics techniques, will be beneficial across genomics dep ....Novel bioinformatics approaches for biological inference from comparative genomics data. Unlocking the potential of the human and other genome sequences depends almost entirely upon comparative genomics techniques. We will develop powerful bioinformatic models, implemented as high-performance computing solutions, for the examination of gene sequences. Improving these models, which represent the initial building block for all comparative genomics techniques, will be beneficial across genomics dependent industries. A major outcome from this work will be an integrated software/hardware product optimised for statistical examination of very large-scale genomics data.Read moreRead less
A role for Cited2, Transforming Growth Factor-beta and matrix metaloproteinases in trophoblast invasion and placenta formation. The placenta is essential for the growth and development of the fetus, and if it fails to form correctly during pregnancy, it can have dramatic effects that can result death in utero, or adult onset diseases. Our research aims to understand how one protein functions in placenta formation. We will also investigate how this protein works at the molecular level in a proces ....A role for Cited2, Transforming Growth Factor-beta and matrix metaloproteinases in trophoblast invasion and placenta formation. The placenta is essential for the growth and development of the fetus, and if it fails to form correctly during pregnancy, it can have dramatic effects that can result death in utero, or adult onset diseases. Our research aims to understand how one protein functions in placenta formation. We will also investigate how this protein works at the molecular level in a process that enables single cells to respond to molecules sent from a distance by other cells (TGF-beta signalling). This process is also very important for a host of other biological processes relevant to human health, including cancer.Read moreRead less
The development and evolution of the pelvic girdle in basal gnathostomes. Comparing the development of muscles, cartilage and bone in representatives of all three major groups of fish will provide information as to how structures evolved but also how the adult morphology is distributed in phylogeny. Because so little is known about the genetic mechanisms underlying the formation of the pelvic girdle in fish, it is important to start studying a model animal such as the zebrafish. The pathways unc ....The development and evolution of the pelvic girdle in basal gnathostomes. Comparing the development of muscles, cartilage and bone in representatives of all three major groups of fish will provide information as to how structures evolved but also how the adult morphology is distributed in phylogeny. Because so little is known about the genetic mechanisms underlying the formation of the pelvic girdle in fish, it is important to start studying a model animal such as the zebrafish. The pathways uncovered have the potential to describe mechanisms common to all jawed vertebrates, not only common to fish. Understanding the mechanisms that generate major morphological transition in the vertebrate lineage necessarily informs us about our own evolutionRead moreRead less
Specification and evolution of vertebrate appendicular muscle. Previously we have determined that two different developmental mechanisms are utilised to make the muscles present within the fins and limbs of distinct vertebrate species. This proposal is concerned with determining the morphogenetic, evolutionary and molecular basis for these two different developmental modes. To do this we will to extend our observations more widely to examine muscle formation in both the paired fins in a phyloge ....Specification and evolution of vertebrate appendicular muscle. Previously we have determined that two different developmental mechanisms are utilised to make the muscles present within the fins and limbs of distinct vertebrate species. This proposal is concerned with determining the morphogenetic, evolutionary and molecular basis for these two different developmental modes. To do this we will to extend our observations more widely to examine muscle formation in both the paired fins in a phylogenetically diverse context. We further hope to determine the underlying genetic basis for these different morphologies by developing techniques to examine their formation in a number of embryonic contexts.Read moreRead less