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Novel kinases: How do they regulate epithelial ion transport, and what is their role in epithelial function? The project will produce the knowledge of fundamental physiology that will lead to novel approaches for treating respiratory and gastrointestinal infections and cystic fibrosis, as well as for the accumulation of fluid in the lungs and abdomen that accompany many advanced malignancies. It thus has the potential to have a significant economic and social impact in Australia and internation ....Novel kinases: How do they regulate epithelial ion transport, and what is their role in epithelial function? The project will produce the knowledge of fundamental physiology that will lead to novel approaches for treating respiratory and gastrointestinal infections and cystic fibrosis, as well as for the accumulation of fluid in the lungs and abdomen that accompany many advanced malignancies. It thus has the potential to have a significant economic and social impact in Australia and internationally. Furthermore, it will provide advanced training in research methods to Australian scientists, equipping them to undertake challenging and interesting positions in the medical and life sciences and beyond.Read moreRead less
Structural determination of respiratory membrane protein complexes by X-ray crystallography. Membrane proteins form only 0.3% of the available protein structures in the protein data bank (PDB), yet 30% of the proteins in the human genome and 50% of human drug targets are membrane proteins. We have managed to increase the success rate through rational screening and development of new crystallization screens, with downstream implications for basic and medical research. Results from this proposal w ....Structural determination of respiratory membrane protein complexes by X-ray crystallography. Membrane proteins form only 0.3% of the available protein structures in the protein data bank (PDB), yet 30% of the proteins in the human genome and 50% of human drug targets are membrane proteins. We have managed to increase the success rate through rational screening and development of new crystallization screens, with downstream implications for basic and medical research. Results from this proposal will receive international recognition and will encourage more research in this field, attracting international funding, and create new research opportunities. Read moreRead less
A new paradigm for surfactant composition and function - how do lungs cope with stress? Our research will increase the understanding of the scope of change and precise molecular interactions occurring in the surfactant lipids and proteins of animals under physiological stress. The novel insights will improve the treatment of lung diseases (such as chronic obstructive pulmonary disease and acute lung injury). We have formed a team of international surfactant researchers all experts in state-of-th ....A new paradigm for surfactant composition and function - how do lungs cope with stress? Our research will increase the understanding of the scope of change and precise molecular interactions occurring in the surfactant lipids and proteins of animals under physiological stress. The novel insights will improve the treatment of lung diseases (such as chronic obstructive pulmonary disease and acute lung injury). We have formed a team of international surfactant researchers all experts in state-of-the-art chemical and biophysical technologies relating to surfactant. These collaborations will bring new technological applications to Australia and provide outstanding cross-disciplinary training for postgraduate students and research staff at the interface between animal physiology, biophysical chemistry and respiratory medicine.Read moreRead less
Environmental control of genetic/phenotypic interactions in lung development: An evolutionary perspective. Vertebrate lungs all contain morphologically and functionally similar lung lining cells. However, the cellular arrangement (i.e. lung morphology) and the function of the surfactant these cells produce, differs dramatically between species. Hence, a subset of highly conserved lung-specific genes coincides with spectacular phenotypic diversity. How has this diversity evolved? Do environmental ....Environmental control of genetic/phenotypic interactions in lung development: An evolutionary perspective. Vertebrate lungs all contain morphologically and functionally similar lung lining cells. However, the cellular arrangement (i.e. lung morphology) and the function of the surfactant these cells produce, differs dramatically between species. Hence, a subset of highly conserved lung-specific genes coincides with spectacular phenotypic diversity. How has this diversity evolved? Do environmental conditions, birth strategy or phylogenetic relationships determine lung phenotype? We will experimentally manipulate developing lungs and cells to demonstrate how environmental conditions (temperature, oxygen, lung-fluid regulation and neuro-hormonal input) promote evolutionary processes by altering gene expression, protein/lipid synthesis, cellular differentiation and hence lung morphology/function in animals with different birth strategies.Read moreRead less
Electrophysiological and Anatomical Characterization of the Coronary Sinus Musculature and its Relationship to the Atria. This series of experiments will characterise the normal coronary sinus musculature and its connectivity to the atria of the heart and establish their electrical relationships. The underlying characteristics of the muscular connections will also be evaluated with a view to possible future manipulations of the system. Understanding normal heart impulse propagation is paramount ....Electrophysiological and Anatomical Characterization of the Coronary Sinus Musculature and its Relationship to the Atria. This series of experiments will characterise the normal coronary sinus musculature and its connectivity to the atria of the heart and establish their electrical relationships. The underlying characteristics of the muscular connections will also be evaluated with a view to possible future manipulations of the system. Understanding normal heart impulse propagation is paramount before we can understand and develop treatments for dealing with heart problems. This information will facilitate the development of techniques to treat and prevent heart rhythm disorders that are a common cause of morbidity in the community.Read moreRead less
Biophysical characterization of protein interactions within a transcription factor network. Gene expression is regulated in part by interactions between pairs and groups of proteins known as transcription factors and co-regulators. These proteins assemble into complexes at gene promoters and enhancers and thereby control the expression of that gene. Little is known at the molecular level of how these complexes form and how different interactions cooperate or compete with each other. In this prop ....Biophysical characterization of protein interactions within a transcription factor network. Gene expression is regulated in part by interactions between pairs and groups of proteins known as transcription factors and co-regulators. These proteins assemble into complexes at gene promoters and enhancers and thereby control the expression of that gene. Little is known at the molecular level of how these complexes form and how different interactions cooperate or compete with each other. In this proposal we aim to define a complex between two transcriptional regulators (HOP and SRF) involved in cardiac development and to begin to define other interactions that make up a transcriptional network essential for development of a normal heart.Read moreRead less
Impact of shear stress on vascular adaptations in humans. Large arteries are important for the delivery of blood and oxygen to organs such as the heart and brain. A primary physiological stimulus which controls the size and function of these crucial arteries is the magnitude of flow or, more accurately, shear force that the inner wall of the artery is exposed to. We have developed novel software which enables non-invasive assessment of arterial wall velocity, diameter and blood flow. We will ass ....Impact of shear stress on vascular adaptations in humans. Large arteries are important for the delivery of blood and oxygen to organs such as the heart and brain. A primary physiological stimulus which controls the size and function of these crucial arteries is the magnitude of flow or, more accurately, shear force that the inner wall of the artery is exposed to. We have developed novel software which enables non-invasive assessment of arterial wall velocity, diameter and blood flow. We will assess the impact of acute and chronic changes in wall flow and shear on arterial size and function. We will also develop new software which measures other aspects of artery wall behaviour. These basic human physiology studies have direct implications for assessment of artery health in humans.Read moreRead less
Oxidative stress-induced alterations of the host erythrocyte by the malaria parasite. The malaria parasite spends part of its lifecycle inside the red blood cells of its host. During this time, the parasite modifies many of the features of the red blood cell and subjects it to high levels of oxidative stress. We will use and develop a variety of fluorescence and microscopic techniques to understand the molecular basis of the alterations in the organization of membrane proteins in malaria parasit ....Oxidative stress-induced alterations of the host erythrocyte by the malaria parasite. The malaria parasite spends part of its lifecycle inside the red blood cells of its host. During this time, the parasite modifies many of the features of the red blood cell and subjects it to high levels of oxidative stress. We will use and develop a variety of fluorescence and microscopic techniques to understand the molecular basis of the alterations in the organization of membrane proteins in malaria parasite-infected red blood cells. We will examine the roles of oxidative stress and of parasite proteins in modulating the properties of the host cell membrane.Read moreRead less
Novel target of amiloride analogues - picornaviral RNA polymerase. Picornaviruses cause a range of diseases such as poliomyelitis, meningitis, myocarditis, hepatitis A, neonatal sepsis and common cold. No antiviral treatment is available for these infections. Nearly 50% of antiviral drugs used in medicine are viral polymerase inhibitors; however picornaviral RNA polymerase has been largely overlooked as a drug target. We have discovered a group of compounds that inhibit picornaviral RNA polymera ....Novel target of amiloride analogues - picornaviral RNA polymerase. Picornaviruses cause a range of diseases such as poliomyelitis, meningitis, myocarditis, hepatitis A, neonatal sepsis and common cold. No antiviral treatment is available for these infections. Nearly 50% of antiviral drugs used in medicine are viral polymerase inhibitors; however picornaviral RNA polymerase has been largely overlooked as a drug target. We have discovered a group of compounds that inhibit picornaviral RNA polymerase. This project aims to define the inhibition mechanism and to evaluate a potential use of these compounds for antiviral drug development.Read moreRead less
Regenerating lizard tails: A model for understanding the process of lymphangiogenesis. In humans, impaired lymphatic drainage in limbs causes the debilitating swelling termed lymphoedema. Lymphoedema affects 500,000,000 people worldwide. In the developed world lymphoedema predominantly results from surgery for cancer, and occurs in approximately 25% of breast cancer patients. We will examine lymph vessel regeneration (lymphangiogenesis) in a naturally regenerating, complex structure (the lizard ....Regenerating lizard tails: A model for understanding the process of lymphangiogenesis. In humans, impaired lymphatic drainage in limbs causes the debilitating swelling termed lymphoedema. Lymphoedema affects 500,000,000 people worldwide. In the developed world lymphoedema predominantly results from surgery for cancer, and occurs in approximately 25% of breast cancer patients. We will examine lymph vessel regeneration (lymphangiogenesis) in a naturally regenerating, complex structure (the lizard tail), to describe the regrowth process and determine the abundance, location, functional properties and molecular control of the new lymphatics. Furthermore, if reptilian lymphatic growth factors can promote lymphangiogenesis in mammals, we can design novel therapeutic approaches using reptilian ligands to promote lymphangiogenesis in lymphoedematous human tissues.Read moreRead less