The function of menin in mammalian development. This project aims to determine the role of a ubiquitous transcriptional co-regulator, menin, in mammalian development. Mice that lack menin through targeted deletion of the gene die during embryogenesis, but the cause is unknown, although is likely to be due to the abnormal expression of genes usually regulated by this factor. We will determine which genes are inappropriately expressed and responsible for the accompanying developmental defects. Thi ....The function of menin in mammalian development. This project aims to determine the role of a ubiquitous transcriptional co-regulator, menin, in mammalian development. Mice that lack menin through targeted deletion of the gene die during embryogenesis, but the cause is unknown, although is likely to be due to the abnormal expression of genes usually regulated by this factor. We will determine which genes are inappropriately expressed and responsible for the accompanying developmental defects. This knowledge will help us understand the process of development in mammals, including birth defects in humans.Read moreRead less
Single minded 1 in neuron development and satiety signalling. An understanding of how Single minded 1 (SIM1) regulates target genes may allow new pharmaceutical approaches to be designed to combat obesity. As Sim1 belongs to a family of closely related gene regulatory proteins which function in early development and homeostasis, deciphering the molecular control mechanisms of Sim1 may help understand how the related factors function in processes such as angiogenesis, response to low oxygen stres ....Single minded 1 in neuron development and satiety signalling. An understanding of how Single minded 1 (SIM1) regulates target genes may allow new pharmaceutical approaches to be designed to combat obesity. As Sim1 belongs to a family of closely related gene regulatory proteins which function in early development and homeostasis, deciphering the molecular control mechanisms of Sim1 may help understand how the related factors function in processes such as angiogenesis, response to low oxygen stress, invasion of environmental pollutants and autism spectrum diseases. The ability to manipulate these factors would be of great benefit in treating a range of disorders, but a thorough molecular understanding of these factors needs be obtained prior to attempting design of pharmaceuticals.Read moreRead less
Evolution of nervous system patterning processes: characterisation of homologs of key Drosophila regulatory genes from the coral Acropora. Defining the common mechanisms of nervous system development is one of the major goals of modern biology, but is presently being addressed largely by comparisons between a few very advanced (and therefore specialised) animals. Comparative data from a lower animal is urgently needed, and will clarify many aspects of nervous system evolution and development. Th ....Evolution of nervous system patterning processes: characterisation of homologs of key Drosophila regulatory genes from the coral Acropora. Defining the common mechanisms of nervous system development is one of the major goals of modern biology, but is presently being addressed largely by comparisons between a few very advanced (and therefore specialised) animals. Comparative data from a lower animal is urgently needed, and will clarify many aspects of nervous system evolution and development. The pioneering work carried out on Acropora in this laboratory suggests that it is perhaps the best choice currently available for this purpose. This project will use Acropora to address fundamental questions about the evolution of nervous system developmental processes.Read moreRead less
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
Characterisation of the novel mitochondrial protein (CABC1/ADCK3) and its role in protecting against oxidative stress. This is the first detailed characterisation and mechanistic study on a protein that protects against oxidative stress and neurodegeneration. Demonstrating the basis for this oxidative stress and its possible contribution to the cellular phenotype will be of benefit in understanding the disease process and ultimately designing approaches to minimise oxidative stress. An investiga ....Characterisation of the novel mitochondrial protein (CABC1/ADCK3) and its role in protecting against oxidative stress. This is the first detailed characterisation and mechanistic study on a protein that protects against oxidative stress and neurodegeneration. Demonstrating the basis for this oxidative stress and its possible contribution to the cellular phenotype will be of benefit in understanding the disease process and ultimately designing approaches to minimise oxidative stress. An investigation of this protein presents an opportunity for the investigator to work at the forefront in this field adding to Australia's scientific leadership in the area. It also represents an ideal project for post-graduate training and is a collaboration between groups in Brisbane and Melbourne. Read moreRead less
Single Minded 2: Cross coupling or specificity within the bHLH/PAS transcription factor family? Understanding the mechanisms of action of SIM2 may lead to novel ideas towards drug development for diseases such as Down syndrome and cancer. The SIM2 protein can interfere with activity of the related Hypoxia Inducible Factor (HIF), a protein important in stress response and recovery from stroke. Understanding the molecular basis of this interference could aid current strategies being used to manipu ....Single Minded 2: Cross coupling or specificity within the bHLH/PAS transcription factor family? Understanding the mechanisms of action of SIM2 may lead to novel ideas towards drug development for diseases such as Down syndrome and cancer. The SIM2 protein can interfere with activity of the related Hypoxia Inducible Factor (HIF), a protein important in stress response and recovery from stroke. Understanding the molecular basis of this interference could aid current strategies being used to manipulate HIF for pharmaceutical benefit.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