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.
Deregulated Cytokine Signalling As A Molecular Bridge Linking The Pathogenesis Of Emphysema To Lung Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$524,820.00
Summary
Lung cancer is the most lethal form of cancer in Australia and worldwide. Although smokers with emphysema are at an increased risk of developing lung cancer, it is becoming apparent that emphysema can predispose to lung cancer independently of cigarette smoking, albeit by unknown mechanisms. Our aim is to combine smoke carcinogen and genetic mouse models of lung cancer with novel mouse strains displaying emphysema to identify the processes which link the pathogenesis of emphysema to lung cancer.
Identifying New Therapeutic Targets For Preventing The Induction And Progression Of COPD
Funder
National Health and Medical Research Council
Funding Amount
$649,314.00
Summary
Smoking leads to lung inflammation that causes emphysema, which is a major health problem in Australia. Once induced there is a progressive decline in health, which continues even after stopping smoking. There are no treatments that halt this decline. Recently small genes have been discovered that control inflammation. We may be able to control these small genes and stop the induction and progression of emphysema. This project may lead to a completely new way of preventing and treating emphysema ....Smoking leads to lung inflammation that causes emphysema, which is a major health problem in Australia. Once induced there is a progressive decline in health, which continues even after stopping smoking. There are no treatments that halt this decline. Recently small genes have been discovered that control inflammation. We may be able to control these small genes and stop the induction and progression of emphysema. This project may lead to a completely new way of preventing and treating emphysema.Read moreRead less
Risk Factors For Asthma, Chronic Bronchitis And Emphysema In Older Adults
Funder
National Health and Medical Research Council
Funding Amount
$330,574.00
Summary
Chronic obstructive pulmonary disease (including chronic bronchitis and emphysema) is a major public health problem in Australia. The main known cause is cigarette smoking, which peaked among Australian men shortly after the second world war. Now that the consequences of this epidemic of smoking are passing, more attention needs to be paid to other causes of the condition. The proposed study will focus on occupational and domestic exposures and dietary factors in older people. Dusty jobs have lo ....Chronic obstructive pulmonary disease (including chronic bronchitis and emphysema) is a major public health problem in Australia. The main known cause is cigarette smoking, which peaked among Australian men shortly after the second world war. Now that the consequences of this epidemic of smoking are passing, more attention needs to be paid to other causes of the condition. The proposed study will focus on occupational and domestic exposures and dietary factors in older people. Dusty jobs have long been associated with COPD. However it is not known to what extent other occupational exposures to fumes and vapours are also responsible. Identifying such jobs would lead to better workplace conditions and prevention of further cases. Workers who have already developed COPD could be more fairly compensated. Similarly if indoor exposures to tobacco smoke and unvented gas appliances were found to play a role, further controls on smoking, flues and improved ventilation could also prevent cases of COPD. It is generally thought that emphysema develops from an imbalance between the oxidative stresses on the lungs and protective enzymes. A diet high in antioxidant vitamins and fish may protect against the development of COPD. If confirmed by this study, it would then be possible to conduct clinical trials of supplementation in smokers at risk of developing COPD. Public nutritional education could reduce the incidence of the condition in the future.Read moreRead less
Molecular Analysis Of Alpha-1-Antitrypsin Misfolding: A Cause Of Alpha-1-antitrypsin Deficiency
Funder
National Health and Medical Research Council
Funding Amount
$255,837.00
Summary
Antitrypsin deficiency occurs in approximately 1 in 1800 live births. It is the most common genetic cause of liver disease in children and the debilitating lung disease emphysema in adults. Antitrypsin is produced in the liver and secreted into the circulation. Its primary role is to inhibit the degradative enzyme elastase which attacks the tissues of the lung. A deficiency in Antitrypsin leads to uncontrolled elastase activity which destroys the lung tissue so causing emphysema. The deficiency ....Antitrypsin deficiency occurs in approximately 1 in 1800 live births. It is the most common genetic cause of liver disease in children and the debilitating lung disease emphysema in adults. Antitrypsin is produced in the liver and secreted into the circulation. Its primary role is to inhibit the degradative enzyme elastase which attacks the tissues of the lung. A deficiency in Antitrypsin leads to uncontrolled elastase activity which destroys the lung tissue so causing emphysema. The deficiency is commonly caused by Antitrypsin being unable to enter the circulation. This is due to mutations within the Antitrypsin molecule which cause the protein to adopt an incorrect three-dimensional structure. This causes the protein to form long chains within the liver, which in turn damage the liver cell. There are no specific treatments for Antitrypsin deficiency, this partly reflects our lack of understanding of the molecular basis of the disease. This project examines the effects of the mutations upon the folding of Antitrypsin so that we can understand how these long protein chains form. Using a range of biochemical techniques we will monitor structural changes within the normal and abnormal proteins as they fold to determine how the mutations disrupt the process. These data will allow us to begin to rationally design inhibitors which will prevent the formation of the long chains, which we hope will aid in the treatment of patients with Antitrypsin deficiency. This increased understanding of Antitrypsin deficiency may also benefit other disease processes where similar protein misfolding occurs such as amyloid and prion diseases.Read moreRead less
The Role Of Glucocorticoids, Retinol And CAMP Signaling In Lung Development And Neonatal Respiratory Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$447,000.00
Summary
Underdeveloped lungs at birth and adult lung diseases (ie emphysema, acute resipratory distress, and asthma) are a major cause of hopitalization and death. The World Health Organization ranks resipratory diseases at number 6 in the global burden of disease. Preterm birth with associated respiratory complications occurs in about 10% of all human births and accounts for 75% of neonatal deaths not associated with congenital abnormalities . Respiratory Distress Syndrome (RDS) is a major complication ....Underdeveloped lungs at birth and adult lung diseases (ie emphysema, acute resipratory distress, and asthma) are a major cause of hopitalization and death. The World Health Organization ranks resipratory diseases at number 6 in the global burden of disease. Preterm birth with associated respiratory complications occurs in about 10% of all human births and accounts for 75% of neonatal deaths not associated with congenital abnormalities . Respiratory Distress Syndrome (RDS) is a major complication in preterm births and the routine antenatal treatment of glucocorticoids has a major benefit in reducing incidence of RDS leading to decreased neonatal mortality. Glucocorticoids improve lung maturation yet their exact detailed role is not fully understood. Other systemic hormones and factors , such as vitamin A (precursor for retinoic acid) are also important in regulating, completing and maintaining proper lung development and function. Vitamin A deficiency alters lung structure and function, and is believed to be a causal factor in chronic lung diseases such as bronchopulmonary dysplasia, frequently problematic to infants. Detailed understanding of how these hormones work in the lung is critical to the future improvement of treatments for respiratory distress at birth and other respiratory conditions (emphysema, asthma) during adult life. We have developed a number of mouse models to study how these hormones work in the lung and allows us to perform investigations not possible in the human system. Using these mouse models of hormone resistance for glucocorticoids, retinoic acid (vitamin A) and cAMP signaling we will study in detail how these hormones work in the developing lung. Outcomes will be detailed knowledge and mechanisms of action that are critical for the design and testing of novel agents and therapies for immature lungs at birth and in adult lung dysfunction and diseaseRead moreRead less
Mechanisms Defining Microfibril And Elastic Fibre Assembly, Structure And Function.
Funder
National Health and Medical Research Council
Funding Amount
$619,721.00
Summary
Elastic fibres are important in tissues such as arteries, lung and skin where they provide elasticity. Disruption of their normal structure and function is a major aspect of common diseases such as atherosclerosis, aneurisms, heart valve prolapse, emphysema, and the congenital disorder, Marfan syndrome. Elastic fibres consist of a core of the protein elastin surrounded by 12 nm glycoprotein microfibrils. During development the microfibrils always appear before the elastin and seem to act as a sc ....Elastic fibres are important in tissues such as arteries, lung and skin where they provide elasticity. Disruption of their normal structure and function is a major aspect of common diseases such as atherosclerosis, aneurisms, heart valve prolapse, emphysema, and the congenital disorder, Marfan syndrome. Elastic fibres consist of a core of the protein elastin surrounded by 12 nm glycoprotein microfibrils. During development the microfibrils always appear before the elastin and seem to act as a scaffold for the deposition of its precursor, tropoelastin. However knowledge of the role of each glycoprotein in the assembly, architecture, function and cell biology of microfibrils and elastic fibres is still very limited. Our laboratory has identified, cloned and characterised several microfibrillar proteins and we are uniquely placed to exploit our expertise and unique range of research tools to elucidate the mechanisms involved in the above processes. The Specific Aims are to determine a) the roles of individual components and associated proteins in microfibril and elastic fibre biology b) the architecture of microfibrils and the relationship of their structural heterogeneity to function during tissue development, c) the mechanisms responsible for microfibril and elastic fibre assembly, and other microfibril interactions with the cell surface, d) the gene regulatory mechanisms controlling expression of individual microfibrillar proteins and e) causative mutations of non-fibrillin genes in Marfan-like congenital disorders. The research will greatly increase our fundamental knowledge of the factors controlling the complex molecular mechanisms involved in microfibril assembly and elastic fibre formation, including the roles of individual microfibril-associated proteins, cell surface receptors, cellular processing, and gene regulation of these processes during normal development, which is essential before the full role of elastic fibres in major diseases can be understood.Read moreRead less