Role of suppressor of cytokine signalling proteins (SOCS3) in defective muscle repair and ageing. Old muscles are slower and weaker than young muscles, they are injured more easily and they repair less successfully. This proposal investigates the role of SOCS3-signalling in muscle repair, ultimately to improve healing and to promote healthy ageing that will enable older Australians to enjoy a better quality of life.
The foot soldiers of the immune system, the white blood cells, constantly march through the body seeking out invaders, but kept in check by the barrier of endothelial cells that lines the inside of blood vessels. When infection occurs, molecular messages are transmitted amongst the white cells and between white cells and edothelium, to activate the immune cells to pass out of the blood vessels and mount a defence. Unfortunatley, the activation system sometimes goes awry, resulting in inflammator ....The foot soldiers of the immune system, the white blood cells, constantly march through the body seeking out invaders, but kept in check by the barrier of endothelial cells that lines the inside of blood vessels. When infection occurs, molecular messages are transmitted amongst the white cells and between white cells and edothelium, to activate the immune cells to pass out of the blood vessels and mount a defence. Unfortunatley, the activation system sometimes goes awry, resulting in inflammatory or allergic disease, such as arthritis or asthma. This team of researchers from the Hanson Institute in Adelaide, combining expertise in molecular and cell biology, protein chemestry, structual biology and animal models, has been working together for over 10 years, investigating the molecular mechanisms involved in controlling the formation and activities of blood vessels and white blood cells. This program seeks to further that understanding, and to develop drugs that have the potential of ameliorating the inflammatory condition.Read moreRead less
The insulin-like growth factor system is involved in promoting cancer growth and survival against treatment with chemotherapy. Insulin-like growth factors-I and -II act via cell surface receptors (IGF-1R). Much effort has been applied to blocking the action of insulin-like growth factors via IGF-1R. However, recently a second mechanism has been identified by which the insulin-like growth factors are involved in cancer. Insulin-like growth factor-II can also promote cancer growth and survival via ....The insulin-like growth factor system is involved in promoting cancer growth and survival against treatment with chemotherapy. Insulin-like growth factors-I and -II act via cell surface receptors (IGF-1R). Much effort has been applied to blocking the action of insulin-like growth factors via IGF-1R. However, recently a second mechanism has been identified by which the insulin-like growth factors are involved in cancer. Insulin-like growth factor-II can also promote cancer growth and survival via an alternative form of the insulin receptor. We will join with our international collaborator to bring together a team of biochemists and protein structural biologists who are world leaders in understanding protein interactions in the insulin and insulin-like growth factor systems. As relatively little is known about this alternate pathway we propose to define the mechanism of binding of insulin-like growth factor-II to the alternate insulin receptor isoform. Using a combination of well-established and novel techniques we will map the interaction. This knowledge will allow design of specific inhibitors to block the action of insulin-like growth factor-II in promotion of cancer cell growth and survival without disruption of the metabolic actions of the insulin receptor.Read moreRead less
A major feature of tumour progression and cardiac hypertrophy (enlarged heart) is accelerated cell growth and protein synthesis. Moreover, increased synthesis of ribosomes (the protein synthetic machinery) is associated with malignancy and hypertrophy suggesting that it may play a causal role in tumour formation and cardiac disease. In support of this, specific inhibitors of both ribosome biogenesis and function are extremely effective at inhibiting the growth of some tumours and vascular smooth ....A major feature of tumour progression and cardiac hypertrophy (enlarged heart) is accelerated cell growth and protein synthesis. Moreover, increased synthesis of ribosomes (the protein synthetic machinery) is associated with malignancy and hypertrophy suggesting that it may play a causal role in tumour formation and cardiac disease. In support of this, specific inhibitors of both ribosome biogenesis and function are extremely effective at inhibiting the growth of some tumours and vascular smooth muscle. This study will examine the mechanisms that regulate ribosome synthesis. Specifically it focuses on a transcription factor termed UBF whose activity we think is critical for the regulation of the synthesis of the ribosomal RNA, the catalytic backbone of the ribosomes. Understanding the molecular mechanism(s) controlling UBF function will lead to a better comprehension of how cells modulate synthesis of functional ribosomes and how this process is deregulated during disease states associated with deregulated protein synthesis and growth such as cardiac hypertrophy and cancer.Read moreRead less
Transcription factor – enhancer – promoter based regulatory networks. This project aims to develop new understanding on how multicellular organisms (including humans) develop, and how mutations in distant regions of the genome can affect human traits. The way the human genome is interpreted by the cellular machinery is still a mystery. We have a reference sequence and know where the majority of coding genes are, but we are far from understanding how the genome is regulated to generate the divers ....Transcription factor – enhancer – promoter based regulatory networks. This project aims to develop new understanding on how multicellular organisms (including humans) develop, and how mutations in distant regions of the genome can affect human traits. The way the human genome is interpreted by the cellular machinery is still a mystery. We have a reference sequence and know where the majority of coding genes are, but we are far from understanding how the genome is regulated to generate the diversity of cell types in our bodies. Enhancer regions interact with proximal promoters to regulate gene expression level and tissue-specificity. This project aims to develop transcriptional regulatory network models using high throughput chromatin interaction data and expression perturbation to link promoter and enhancers genome-wide.Read moreRead less
Central Muscarinic Receptors as Novel Drug Targets for Parkinson's Disease and Schizophrenia. Psychiatric and neurodegenerative disorders such as schizophrenia and Parkinson's disease are linked to alterations in the activity of neurons in the brain containing the chemical dopamine. Other types of brain neurons containing the chemical acetylcholine regulate dopamine neuron activity by acting on acetylcholine receptors located on dopamine neurons. We aim to determine how these important recepto ....Central Muscarinic Receptors as Novel Drug Targets for Parkinson's Disease and Schizophrenia. Psychiatric and neurodegenerative disorders such as schizophrenia and Parkinson's disease are linked to alterations in the activity of neurons in the brain containing the chemical dopamine. Other types of brain neurons containing the chemical acetylcholine regulate dopamine neuron activity by acting on acetylcholine receptors located on dopamine neurons. We aim to determine how these important receptors regulate dopamine neuron activity using genetically modified mice deficient in acetylcholine receptors, together with newly developed physiological methods and new acetylcholine receptor drugs. These studies will foster the design of novel acetylcholine receptor drugs as effective pharmaceutical treatments of neurological and psychiatric disorders related to brain dopamine dysfunction.Read moreRead less
A tale of two genomes: integrating mitochondrial biogenesis into the cell cycle and metabolic control. The human genome is cordoned into two distinct compartments in our cells. Most genes are in the nucleus, while a distinct set of genes are held within our mitochondria. Using yeast as a model organism, this project will provide a holistic view of how expression of the two genomes is coordinated.
Muscarinic Receptor Regulation of Dopamine Reward Pathways in the Brain. Human disorders such as schizophrenia and drug addiction are linked to alterations in the activity of neurons in the brain containing the chemical dopamine. Other types of brain neurons containing the chemical acetylcholine regulate the activity of dopamine neurons by acting on acetylcholine receptors located on dopamine neurons. We aim to examine how dopamine neuron activity is regulated by these receptors using newly de ....Muscarinic Receptor Regulation of Dopamine Reward Pathways in the Brain. Human disorders such as schizophrenia and drug addiction are linked to alterations in the activity of neurons in the brain containing the chemical dopamine. Other types of brain neurons containing the chemical acetylcholine regulate the activity of dopamine neurons by acting on acetylcholine receptors located on dopamine neurons. We aim to examine how dopamine neuron activity is regulated by these receptors using newly developed physiological methods together with a new acetylcholine receptor drug. We also aim to assess the suitability of mice genetically modified to be deficient in acetylcholine receptors as animal models of dopamine dysfunction related to schizophrenia and drug addiction.Read moreRead less
Selective secretion: a novel mechanism of protein trafficking and its role in Phytophthora pathogenicity. Agriculturally important crops and over 3,000 Australian native plants are susceptible to diseases caused by Phytophthora, fungus-like pathogens that live in the soil. Economic losses exceed $200m pa and natural ecosystems are being destroyed on a vast scale. Phytophthora control depends upon a limited number of chemical inhibitors to which resistance has already emerged. New control stra ....Selective secretion: a novel mechanism of protein trafficking and its role in Phytophthora pathogenicity. Agriculturally important crops and over 3,000 Australian native plants are susceptible to diseases caused by Phytophthora, fungus-like pathogens that live in the soil. Economic losses exceed $200m pa and natural ecosystems are being destroyed on a vast scale. Phytophthora control depends upon a limited number of chemical inhibitors to which resistance has already emerged. New control strategies are urgently needed. This research will investigate a novel mechanism for release of infection material recently discovered in Phytophthora cells, and will increase our understanding of how Phytophthora infects host plants, providing vital information required for the development of new, environmentally-safe inhibitors. Read moreRead less