Molecular Mechanisms Of Wasting In Experimental COPD
Funder
National Health and Medical Research Council
Funding Amount
$389,521.00
Summary
Chronic obstructive pulmonary disease (COPD) is a major global health problem and has been predicted to become the third largest cause of death in the world by 2020. Cigarette smoking is the major cause of COPD and accounts for more than 95% of cases in industrialized countries. Currently no therapies exist to halt the inevitable progression of the disease. To date most of the research has focused on the aspects of this disease which result in destruction of the lung however it is becoming incre ....Chronic obstructive pulmonary disease (COPD) is a major global health problem and has been predicted to become the third largest cause of death in the world by 2020. Cigarette smoking is the major cause of COPD and accounts for more than 95% of cases in industrialized countries. Currently no therapies exist to halt the inevitable progression of the disease. To date most of the research has focused on the aspects of this disease which result in destruction of the lung however it is becoming increasingly evident that COPD is a disease of multiple organs. Until recently it had been widely believed that the profound loss of exercise tolerance observed in COPD patients was due to impaired gas exchange secondary to lung structural damage. Loss of lean body mass (muscle) is now recognised as a major co-morbidity of COPD and a direct cause of functional impairment with patients suffering marked deteriorations in quality of life, increased mortality, breathlessness and decreased exercise tolerance. Skeletal muscle wasting is a powerful predictor of mortality in COPD, independent of the lung function impairment. Despite the clinical seriousness of muscle wasting and suggestive evidence that it may be reversible, little is known about the pathogenic mechanisms. Therefore the goal of this project is to use experimental models of COPD to identify the molecular basis of wasting, in order to restore skeletal muscle homeostasis. The insights gained from this research proposal may lead to the identification of potentially novel targets for the prevention and reversal of the debilitating and life threatening effects of skeletal muscle wasting in COPD. For the COPD patient this has the potential to increase quality of life, functional ability and life expectancy.Read moreRead less
This project will examine new ways in which the major effector cells of allergic inflammation and asthma are regulated by novel S100 protein mediators. We find two natural proteins of the innate immune system, present in cells in the lungs of patients with acute asthma. These have apparently opposing activates: one, S100A12, activates mast cells to release mediators that trigger asthma attack. We will characterise how this proteins is regulated in eosinophils, key cells in asthma. Because mast c ....This project will examine new ways in which the major effector cells of allergic inflammation and asthma are regulated by novel S100 protein mediators. We find two natural proteins of the innate immune system, present in cells in the lungs of patients with acute asthma. These have apparently opposing activates: one, S100A12, activates mast cells to release mediators that trigger asthma attack. We will characterise how this proteins is regulated in eosinophils, key cells in asthma. Because mast cells reside in almost all body tissues and are also important mediators of host responses to allergy, infection and in chronic inflammation such as rheumatoid arthritis and psoriasis, our studies may indicate novel and unexpected ways in which they are activated. A second S100 protein (S100A8) is an efficient scavenger of oxidants that can cause damage to the lung. We find both S100A12 and S100A8 that has been modified by oxidants, in sputum from pateints with asthma. In addition to its anti-oxidant effects, S100A8 can downregulate production of some of the inflammatory mediators that promote allergy and asthma. This is an important finding that will help us understand how drugs used in treatment, such as steroids, are acting. We will generate a mouse expressing this protein in its lungs and determine how this affects normal lungs and the course of asthma. If, as we expect, asthma is reduced, we will have found a novel new pathway that is important in the resolution of asthma. Results from this project will provide new knowledge concerning mechanisms of regulation in allergy and asthma and may lead to the design of novel strategies to regulate the process. Results will have broader ramifications applicable to other chronc inflammatory where these proteins are expressed. We have new reagents that could also assist in the diagnosis of these conditions and may be useful for monitoring treatment.Read moreRead less
Epithelial-Mesenchymal Cell Communication; Towards New Therapeutic Targets For Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$794,596.00
Summary
Fibrosis causes disability and death with millions of people affected each year. Current treatments are limited and there is a need to better understand the changes that drive fibrosis. In this study we will investigate how cells communicate to initiate and drive fibrosis. Using readily available drugs we will test new ways to alter cell communication to stop the disease and thus, develop a common and effective therapy that will change the future for people living with fibrosis.
The Link Between Vitamin D Deficiency And Chronic Lung Disease Is Due To Increased Airway Smooth Muscle
Funder
National Health and Medical Research Council
Funding Amount
$644,067.00
Summary
Vitamin D deficiency is a global public health problem. It is becoming increasingly evident that vitamin D deficiency increases the severity of chronic lung disease. In this study we propose to examine a mechanism that we think clearly explains this association. These studies are critical to understanding how deficiencies in key nutrients can impact on chronic lung disease and will provide the data necessary to guide public health policy to reduce the burden of disease in the community.
Targeting An Epigenetic Silencing Pathway To Treat Allergic Asthma
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Asthma affects around 11% of the Australian population and costs the health care system around $28 billion. Unfortunately there is still no cure and treatments have not changed for decades. This project aims to discover new drugs to treat asthma by re-wiring the cells of the immune system which cause the disease.
Regional Mechanisms Of Ventilator Induced Lung Injury: Insights From Dynamic Lung Imaging
Funder
National Health and Medical Research Council
Funding Amount
$623,323.00
Summary
Mortality rates due to acute respiratory distress syndrome (ARDS) are high (>30%). While ARDS requires mechanical ventilation as a lifesaving intervention, it is clear that mechanical ventilation itself can contribute to the high mortality rates. We will use a new lung imaging technology (CTXV) to visualize the damage that occurs to the lung as a result of mechanical ventilation in order to design better ventilation strategies and reduce mortality rates in these critically ill patients.
Targeting Remodelling In Chronic Obstructive Pulmonary Disease (COPD), Chronic Asthma And Idiopathic Pulmonary Fibrosis (IPF)
Funder
National Health and Medical Research Council
Funding Amount
$386,634.00
Summary
Lung diseases (emphysema, asthma & pulmonary fibrosis) are major burdens on Australian community and economy. Airway remodelling/wounding is a key feature of all these diseases. Patients experience severe breathlessness seriously impacting quality of life and frequently leading to death. We will assess the potential of new targets (including IL-33), & therapy in suppressing wounding in experimental models. This may lead to a new treatment to reverse or prevent lung diseases.
Restoring Skeletal Muscle In An Experimental Model Of COPD By Targeting The IGF-1-myostatin-macrophage Axis
Funder
National Health and Medical Research Council
Funding Amount
$508,183.00
Summary
Most people think that the serious disabilities of COPD (emphysema) patients follows damage to their lungs but wasted muscles may be even more important. We can not regrow lung but we have found a way that might help regrow muscle. We plan to use stem cells to make one of the body's own cells called 'macrophages' and genetically engineer these cells to help deliver healing proteins directly into the muscle. Making muscle stronger will help COPD patients live longer and improve quality of life.
DEFINING SUBPOPULATIONS OF PATHOGENIC MACROPHAGES UNDERLYING LUNG DISEASES
Funder
National Health and Medical Research Council
Funding Amount
$640,496.00
Summary
Chronic obstructive pulmonary disease (COPD) is a serious lung disease that afflicts over 1 million people in Australia and adenocarcinoma is a common fatal lung cancer; both are typically caused by cigarette smoking, and macrophage-rich inflammation is a hallmark feature. Macrophages can destroy lung tissue and promote cancer development. Herein we will identify and profile macrophage subpopulations that are associated with lung inflammation and cancer to identify therapeutic targets that may y ....Chronic obstructive pulmonary disease (COPD) is a serious lung disease that afflicts over 1 million people in Australia and adenocarcinoma is a common fatal lung cancer; both are typically caused by cigarette smoking, and macrophage-rich inflammation is a hallmark feature. Macrophages can destroy lung tissue and promote cancer development. Herein we will identify and profile macrophage subpopulations that are associated with lung inflammation and cancer to identify therapeutic targets that may yield novel intervention strategies.Read moreRead less