Function and redundancy of SOX genes in the mammalian sex determination pathway. We are studying a mouse model of abnormal sex organ development in which genetically female mice develop as males. Our basic research program will lead to greater understanding of the genetic switch controlling the formation of male and female characteristics. This research should in turn provide insight into the causes of defects in patients with disorders of sex development, helping to inform the difficult clinica ....Function and redundancy of SOX genes in the mammalian sex determination pathway. We are studying a mouse model of abnormal sex organ development in which genetically female mice develop as males. Our basic research program will lead to greater understanding of the genetic switch controlling the formation of male and female characteristics. This research should in turn provide insight into the causes of defects in patients with disorders of sex development, helping to inform the difficult clinical decisions that need to be made for their treatment, and ultimately leading to better management and therapeutic strategies. Our studies may also provide unique methods to control the exotic mouse population, using the daughterless strategy.Read moreRead less
Structural and Functional Aspects of the Allosteric Regulation of Pyruvate Carboxylase by Acyl-CoA Compounds. Pyruvate carboxylase occupies a central location in intermediary metabolism catalysing the formation of oxaloacetate, a key component of the Krebs' tricarboxylic acid cycle especially in its synthetic modes in gluconeogenesis, lipogenesis and in the synthesis of neurotransmitters.
This project aims: (i) To produce crystals of pyruvate carboxylase for determining its structure by X-ra ....Structural and Functional Aspects of the Allosteric Regulation of Pyruvate Carboxylase by Acyl-CoA Compounds. Pyruvate carboxylase occupies a central location in intermediary metabolism catalysing the formation of oxaloacetate, a key component of the Krebs' tricarboxylic acid cycle especially in its synthetic modes in gluconeogenesis, lipogenesis and in the synthesis of neurotransmitters.
This project aims: (i) To produce crystals of pyruvate carboxylase for determining its structure by X-ray diffraction; (ii) To use affinity-labelling to determine the amino acid residues in the binding site of the enzyme's allosteric activator, acetyl-CoA; (iii) To construct chimeric enzymes from different species to define regions of the enzyme which affect its responses to its important allosteric activator, acetyl-CoA.
Read moreRead less
The role of the neuronal Hu proteins in the regulation of the BMP signalling pathway. We aim to understand the critical decision of a neural progenitor to commit to becoming a neuron. The BMP signalling pathway is central in this decision. Neural progenitors appear to become insensitive to BMP signals, and this lack of signalling leads to neuronal differentiation. We hypothesise that neuronal identity is regulated by an unusual genetic switch- the translational regulation by the neuronal Hu pr ....The role of the neuronal Hu proteins in the regulation of the BMP signalling pathway. We aim to understand the critical decision of a neural progenitor to commit to becoming a neuron. The BMP signalling pathway is central in this decision. Neural progenitors appear to become insensitive to BMP signals, and this lack of signalling leads to neuronal differentiation. We hypothesise that neuronal identity is regulated by an unusual genetic switch- the translational regulation by the neuronal Hu proteins of two proteins in the BMP pathway. Verification of a post-transcriptional regulatory mechanism for cell fate determination would be a major discovery, and may prompt investigation of how to harness the neuron-inducing function of the Hu proteins to address the therapeutic need for new neurons in neurologic diseases.Read moreRead less
Many Ys in monotremes: multiple sex chromosomes and sex determination in platypus and echidna. Platypus and Echidna are Australian icons, even featuring on our coins. Their unusual biology and ancient relationship to humans make them unique for understanding the mammalian genome, as demonstrated by our recent discovery of ten sex chromosomes in platypus that link mammal and bird sex. Still little is known about their genome, embryo development and how sex is determined. We will identify new gene ....Many Ys in monotremes: multiple sex chromosomes and sex determination in platypus and echidna. Platypus and Echidna are Australian icons, even featuring on our coins. Their unusual biology and ancient relationship to humans make them unique for understanding the mammalian genome, as demonstrated by our recent discovery of ten sex chromosomes in platypus that link mammal and bird sex. Still little is known about their genome, embryo development and how sex is determined. We will identify new genes on all ten sex chromosomes and investigate how they determine sex. The set up of an Australian Monotreme Resource Centre will be crucial for this research and attract worldwide high profile collaborations. We will answer important general questions in monotreme biology and contribute to our understanding of sexual abnormalities in humans.Read moreRead less
Truncating presenilin mutations and their effects on gamma-secretase activity, tau and beta-catenin - insights into Alzheimers disease and cancer. Cancer and dementia are primarily afflictions of the aged and are increasingly important in an aging Australian population. 95% of all Alzheimer's disease is spontaneous (not inherited) but we know little about the molecular mechanisms underlying it. Our discovery that truncated presenilin proteins potently inhibit normal protein function suggests tha ....Truncating presenilin mutations and their effects on gamma-secretase activity, tau and beta-catenin - insights into Alzheimers disease and cancer. Cancer and dementia are primarily afflictions of the aged and are increasingly important in an aging Australian population. 95% of all Alzheimer's disease is spontaneous (not inherited) but we know little about the molecular mechanisms underlying it. Our discovery that truncated presenilin proteins potently inhibit normal protein function suggests that changes in presenilin function in aged cells might be a common molecular link between spontaneous and inherited Alzheimer's disease and could contribute to frontotemporal dementia and cancer. Our research will show whether this phenomenon might provide a breakthrough in our understanding of these diseases and be a productive area for research into their amelioration and/or prevention.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
New Insights into the Structure and Function of Pyruvate Carboxylase. Pyruvate carboxylase plays an essential roles in insulin secretion by pancreatic islets and in normal brain function, but excess expression of this enzyme in liver and adipose tissue is associated with diabetes and obesity.
Understanding the function of each structural feature in the reaction mechanism of an enzyme is essential to designing safe and effective pharmaceuticals that are required to modulate its activity.
Th ....New Insights into the Structure and Function of Pyruvate Carboxylase. Pyruvate carboxylase plays an essential roles in insulin secretion by pancreatic islets and in normal brain function, but excess expression of this enzyme in liver and adipose tissue is associated with diabetes and obesity.
Understanding the function of each structural feature in the reaction mechanism of an enzyme is essential to designing safe and effective pharmaceuticals that are required to modulate its activity.
This project, which will use cutting edge techniques in an experimental model, seeks to characterise this important enzyme's function so that better treatments can be developed in future for diabetes and obesity.
Read moreRead less
A genomic approach to the mechanism of meiotic recombination in Neurospora. Recombination shuffles DNA sequences between homologous chromosomes during the reduction division in the life cycle of higher organisms. Along with mutation, it is a key process in evolution. Understanding of the molecular processes involved in recombination is largely based on yeast, which is intolerant of significant levels of sequence mismatch, limiting the resolution of analyses of normal recombination events. We hav ....A genomic approach to the mechanism of meiotic recombination in Neurospora. Recombination shuffles DNA sequences between homologous chromosomes during the reduction division in the life cycle of higher organisms. Along with mutation, it is a key process in evolution. Understanding of the molecular processes involved in recombination is largely based on yeast, which is intolerant of significant levels of sequence mismatch, limiting the resolution of analyses of normal recombination events. We have shown that Neurospora, like other less tractable multicellular eukaryotes, is tolerant of sequence mismatch, allowing high resolution analysis of individual recombination events. This project will build on fundamental advances we have already made in understanding how recombination occurs.Read moreRead less
Defining New Building Blocks for the Construction of Artificial Genetic Circuits. By characterising the components of a natural genetic switch, we will make available a set of well defined genetic building blocks for construction of rationally designed biological circuits. The ability to build such circuits would have significant economic benefit in areas such as metabolic engineering, to improve the efficiency of production of natural compounds from micro-organisms, and in biomedicine, for the ....Defining New Building Blocks for the Construction of Artificial Genetic Circuits. By characterising the components of a natural genetic switch, we will make available a set of well defined genetic building blocks for construction of rationally designed biological circuits. The ability to build such circuits would have significant economic benefit in areas such as metabolic engineering, to improve the efficiency of production of natural compounds from micro-organisms, and in biomedicine, for the controlled release of therapeutic compounds. The involvement of Honours and Ph.D students in this project will expose the next generation of Australian scientists to this emerging discipline. International collaboration leading to publications in high impact scientific journals will enhance Australia's scientific reputation.Read moreRead less
Plasticity of gastrointestinal vagal afferents. The aim of this project is to identify how leptin modulates specific subtypes of vagal afferent within the gut and the plasticity of this system under different dietary conditions. This proposed project will substantially increase understanding of the interactions between leptin, known to influence food intake, and vagal afferent satiety signals. It will also increase understanding of how these interactions alter in obesity and ultimately provide t ....Plasticity of gastrointestinal vagal afferents. The aim of this project is to identify how leptin modulates specific subtypes of vagal afferent within the gut and the plasticity of this system under different dietary conditions. This proposed project will substantially increase understanding of the interactions between leptin, known to influence food intake, and vagal afferent satiety signals. It will also increase understanding of how these interactions alter in obesity and ultimately provide targets and/or concepts for the pharmacotherapy of obesity.Read moreRead less