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
A Novel Cytokine-receptor Survival Axis In Chronic Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$424,731.00
Summary
Cancer cells grow and survive in an unrestrained manner. Current therapies target cancer growth, however they permit the long-term survival of some cancer cells and increase the possibility of drug resistance and disease relapse. We have identified a new molecular switch that is constitutively activated (unregulated) in leukemia. Targeting specific components of this unregulated cell survival may provide new and improved approaches for the development of therapeutics in the treatment of leukemia
Genetic Approaches To Understand How Imbalanced Cytokine Signalling Drives The Pathogenesis Of Emphysema
Funder
National Health and Medical Research Council
Funding Amount
$519,715.00
Summary
Emphysema is a major component of Chronic Obstructive Pulmonary Disease (COPD), the fifth leading cause of death in Australia for which there is no effective treatment. We have discovered a specific mutation in a gene called gp130 that results in the formation of emphysema in mice. This finding allows us to understand the exact mechanisms by which this mutation causes emphysema, and therefore has the potential to uncover new strategies to design novel therapies against emphysema in humans.
High Resolution EM Tomography of Specialised Plasma Membrane Domains. This project will provide National benefits in two major areas. Firstly, these studies will greatly increase our understanding of the cellular structures which are crucial to the functioning of cells in the body. Understanding the structure of the components of animal cells in three dimensions will provide long-term benefits in the quest to understand how a cell works in health and what goes wrong in disease. Secondly, this pr ....High Resolution EM Tomography of Specialised Plasma Membrane Domains. This project will provide National benefits in two major areas. Firstly, these studies will greatly increase our understanding of the cellular structures which are crucial to the functioning of cells in the body. Understanding the structure of the components of animal cells in three dimensions will provide long-term benefits in the quest to understand how a cell works in health and what goes wrong in disease. Secondly, this project will allow us to develop the new method of electron microscope tomography and apply it to a crucial question in biology. This will be a vital technique for Australian investigators in the coming years and this project will allow scientists and students to be trained in these state-of-the-art techniques.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
Understanding The Role Of Tec In Fcgamma Receptor Mediated Phagocytosis
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
The recognition and destruction of bacterial pathogens and other foreign particles by specific immune cells (macrophages) is principally mediated by the Fcgamma class of cell surface antibody receptors. This proposal aims to understand the molecular mechanisms which link receptor activation to the cellular rearrangements required to invaginate or swallow the offending particle. We have used immunofluorescent microscopy and biochemical methods to show that the intracellular tyrosine kinase Tec is ....The recognition and destruction of bacterial pathogens and other foreign particles by specific immune cells (macrophages) is principally mediated by the Fcgamma class of cell surface antibody receptors. This proposal aims to understand the molecular mechanisms which link receptor activation to the cellular rearrangements required to invaginate or swallow the offending particle. We have used immunofluorescent microscopy and biochemical methods to show that the intracellular tyrosine kinase Tec is an important component of the phagocytosis mechanism. Here we plan to use highly selective gene targeting methods to generate a mouse cell culture model system which is devoid of Tec protein. This will allow us to determine whether Tec is essential for Fcgamma-mediated phagocytosis. Reintroduction of mutant versions of the Tec protein into this null background will provide detailed information on the molecular partners of Tec and the individual roles of the various domains within the Tec protein. By studying the molecular mechanism of phagocytosis, we expect to gain an understanding of how to influence the Fcgamma signalling pathway, either to enhance the ability to deal with pathogens, or to restrict the consequences of excessive phagocytosis associated with autoimmune diseases. Tec is an enzyme likely to play an important role between the Fcgamma receptor and actin cytoskeleton rearrangements and therefore is a potentially important drug target.Read moreRead less
Novel roles for importin alpha proteins in the nucleus. The project will provide fundamental new information about how changes in cell function are influenced by importin (IMP) alpha proteins, both through changes in gene transcription and through alterations to intracellular transport. These findings will inform areas of national priority that include Aging Well, Aging Productively with specific regard to cellular stress responses, and A Healthy Start to Life in the context of production of hea ....Novel roles for importin alpha proteins in the nucleus. The project will provide fundamental new information about how changes in cell function are influenced by importin (IMP) alpha proteins, both through changes in gene transcription and through alterations to intracellular transport. These findings will inform areas of national priority that include Aging Well, Aging Productively with specific regard to cellular stress responses, and A Healthy Start to Life in the context of production of healthy, genetically intact sperm. This project draws together an international team to investigate a phenomenon with implications for new understanding of normal developmental processes and the response of cells/tissues to disease conditions.Read moreRead less
Probing JNK MAPK function with peptide inhibitors. It has generally been accepted that the JNK MAPK family of protein kinases is rapidly and potently activated following the exposure of mammalian cells to stresses and cytokines. However, their biological role has remained controversial. We believe that this problem reflects the lack of a generally applicable and specific JNK MAPK inhibitor. In this project we continue our characterisation of a small peptide inhibitor developed in our laboratori ....Probing JNK MAPK function with peptide inhibitors. It has generally been accepted that the JNK MAPK family of protein kinases is rapidly and potently activated following the exposure of mammalian cells to stresses and cytokines. However, their biological role has remained controversial. We believe that this problem reflects the lack of a generally applicable and specific JNK MAPK inhibitor. In this project we continue our characterisation of a small peptide inhibitor developed in our laboratories. We aim to determine its mechanism of inhibition, the specificity of interaction, and to evolve more effective inhibitors. With these new inhibitors, we can effectively address the biological roles of these kinases.Read moreRead less
Isolation and analysis of novel caspases. Apoptosis is an evolutionarily conserved cellular process which must be tightly controlled for normal development and to avoid disease. Rapid progress has been made recently in the elucidation of apoptotic pathways, but many important components are likely still unknown. The caspases constitute the effector arm of apoptotic signalling pathways and some members play important roles in cytokine maturation. We aim to identify novel caspases using an innovat ....Isolation and analysis of novel caspases. Apoptosis is an evolutionarily conserved cellular process which must be tightly controlled for normal development and to avoid disease. Rapid progress has been made recently in the elucidation of apoptotic pathways, but many important components are likely still unknown. The caspases constitute the effector arm of apoptotic signalling pathways and some members play important roles in cytokine maturation. We aim to identify novel caspases using an innovative technique, and to characterise their function and regulation. Molecules identified in this project may be candidate targets for therapies which modulate apoptosis for treatment or prevention of disease, or diagnostic reagent development.Read moreRead less
Defining in molecular terms cis-inhibition as a means to inhibit Notch signaling. Normal development of a baby and our health after birth is dependent on how our cells behave. Signals move between cells and within them to tell them what to do. Proteins interacting with other proteins mostly transmit these signals. This research focuses on a protein named Notch and the signals that it transmits. Notch functions in normal processes, such as blood vessel formation; but abnormal signaling causes and ....Defining in molecular terms cis-inhibition as a means to inhibit Notch signaling. Normal development of a baby and our health after birth is dependent on how our cells behave. Signals move between cells and within them to tell them what to do. Proteins interacting with other proteins mostly transmit these signals. This research focuses on a protein named Notch and the signals that it transmits. Notch functions in normal processes, such as blood vessel formation; but abnormal signaling causes and/or contributes to pathological situations such as degenerative disease and cancer. We are working to understand how the Notch signal is made and how to control it when it is abnormal. This will allow new medications to be developed to help people who have cancer and other Notch-related illnessesRead moreRead less