Altered Gp130-mediated Signalling In The Regulation Of Pulmonary Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$373,956.00
Summary
Pulmonary fibrosis is a chronic diffuse interstitial lung disease often of unknown cause, characterised pathologically by inflammation and fibrosis of the lung tissue. The prognosis is poor with a 50% mortality at five years after diagnosis and considerable morbidity during those years. Previous investigations have documented the role for inflammation in the development of pulmonary fibrosis and current therapeutic strategies are aimed at suppressing the inflammation using anti- inflammatory dru ....Pulmonary fibrosis is a chronic diffuse interstitial lung disease often of unknown cause, characterised pathologically by inflammation and fibrosis of the lung tissue. The prognosis is poor with a 50% mortality at five years after diagnosis and considerable morbidity during those years. Previous investigations have documented the role for inflammation in the development of pulmonary fibrosis and current therapeutic strategies are aimed at suppressing the inflammation using anti- inflammatory drugs, almost exclusively steroids. The effectiveness of steroids is variable although generally poor and can be associated with significant side effects suggesting that other approaches need to be considered. Data generated over the past decade also have established the concept that the molecular processes underlying the development of fibrosis may represent a new opportunity for therapeutic intervention. This project will build on previous studies examining the effects of a family of molecules called cytokines that signal through gp130 as critical determinants of disease susceptibility and progression. gp 130 is a shared component in the receptor complexes for IL-6 family cytokines and can signal down two major pathways. We have shown that the development of lung fibrosis depends on which specific signalling pathway is used. This study will determine how fibrosis is controlled by these pathways. Our data raises the possibility of developing pharmacological manipulators of gp130 signalling pathways that would suppress fibrosis but leave normal cellular defense mechanisms necessary for host defense in the lung intact.Read moreRead less
The Role Of The Hedgehog Signaling Pathway In Asbestos Associated Malignant Mesothelioma
Funder
National Health and Medical Research Council
Funding Amount
$563,554.00
Summary
Mesothelioma is a aggressive asbestos related cancer mainly of the lung with no effective treatment. Evidence is pointing to the reactivation and aberrant expression of developmental signalling pathways such as the hedgehog signalling pathway as critical to the pathogenesis of certain types of cancer. This study will determine if mesothelioma is regulated by signalling through the hedgehog pathway and by blocking this pathway we will attempt to inhibit tumour growth.
Targeting MiRNA To Inhibit Leukocyte Differentiation: A Novel Anti-inflammatory Approach For The Treatment Of Asthma
Funder
National Health and Medical Research Council
Funding Amount
$601,386.00
Summary
In asthma, the symptoms are caused by an allergic reaction in the lung and the production of inflammatory cells whose maturation is guided by tiny molecules called “microRNAs”. The critical microRNAs will be identified and strategies to block their function developed and tested for their ability to inhibit allergic inflammation to evaluate this approach as a new treatment for asthma.
MKP-1 As A Novel Anti-inflammatory Strategy In Asthma And Airway Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$461,528.00
Summary
Asthma is a chronic disorder where airways are remodelled, or thickened, resulting in poor lung function. Airway remodelling is a consequence of long-term inflammation after multiple episodes of asthma. As the current drugs to treat remodelling have side effects, the aim of this grant is to investigate a novel anti-inflammatory strategy to reverse the development of airway remodelling by increasing the anti-inflammatory protein - MKP-1.
The Role Of Reduced Lung Volume In The Pathogenesis Of Asthma.
Funder
National Health and Medical Research Council
Funding Amount
$275,095.00
Summary
Asthma is a disease for which the cause is not understood. This project is designed to examine the possibilty that breathing at low volumes causes an abnormality in the smooth muscle of the airways that predisposes them to the airway hyperresponsiveness of asthma.
Environmental Influences On Allergic Airways Disease From Birth To 8yrs: Long-term Outcomes Of A Randomised Trial (CAPS)
Funder
National Health and Medical Research Council
Funding Amount
$530,000.00
Summary
The prevalence of asthma in Australia is among the highest in the world yet no trials of primary prevention have been conducted which address the most common known causative agent (housedust mite allergens) and the most common known protective factor (dietary omega-3 fatty acids). Until the effectiveness of interventions which address these factors is certain, it will not be possible to give confident advice about how to prevent asthma. We are applying to continue follow up of the cohort of the ....The prevalence of asthma in Australia is among the highest in the world yet no trials of primary prevention have been conducted which address the most common known causative agent (housedust mite allergens) and the most common known protective factor (dietary omega-3 fatty acids). Until the effectiveness of interventions which address these factors is certain, it will not be possible to give confident advice about how to prevent asthma. We are applying to continue follow up of the cohort of the Childhood Asthma Prevention Study (CAPS) which has been underway since mid-1997. CAPS is a randomised controlled trial in which 616 infants at high risk of developing asthma because of a family history have been enrolled. The interventions include allergen reduction and dietary supplementation with omega-3 fatty acids. The interventions are designed to have maximum effect but be simple to implement by parents. Objective and subjective measurements of exposures, atopy, diet and asthmatic symptoms are being collected at 3 month intervals and at medical assessments when the children are 18 months, 3 and 5 years old. The interventions are stopped at age 5 years. The continued follow up of the cohort to age 8 will enable us to test conclusively if the interventions have had a positive effect. If so, CAPS will form the basis for a nationwide public health campaign which will have the potential to reduce the incidence of childhood asthma in Australia.Read moreRead less
Genetic Dissection Of The Function Of The Src Family Tyrosine Kinase Hck In Inflammatory Lung Disease
Funder
National Health and Medical Research Council
Funding Amount
$323,750.00
Summary
This project aims to identify better and safer treatments for serious, life-threatening inflammatory lung diseases, such as Chronic Obstructive Lung Disease (COPD), which affect over 600 million people worldwide and are a major health problem in Australia. There are no effective treatments that can reverse or slow these diseases. The research is based on our recent discovery that an enzyme called Hck might play a very important role in lung disease. We used mice in which a genetic method had bee ....This project aims to identify better and safer treatments for serious, life-threatening inflammatory lung diseases, such as Chronic Obstructive Lung Disease (COPD), which affect over 600 million people worldwide and are a major health problem in Australia. There are no effective treatments that can reverse or slow these diseases. The research is based on our recent discovery that an enzyme called Hck might play a very important role in lung disease. We used mice in which a genetic method had been used to change Hck into its active form. The mice appeared normal when they were born but developed a progressive lung inflammation that resembled serious human lung diseases. Surprisingly, the mice also displayed enhanced responses to substances from bacteria that can infect the lung - a so-called innate immune response. This led us to conclude that the main problem in the mice was actually enhanced innate immunity - which is usually protective - turning against the lung to cause disease. To understand exactly what controls this fine balance between protection and lung damage, we will use new and sophisticated gene modification methods that allow us to target changes in Hck activity to specific cells that we suspect are the main cause of the disease. In doing so we will add special tags into these cells, so that we can isolate the controlling molecules in the disease process. We are particularly interested in a cell called the macrophage, a major defensive cell in the lung that is also known to be capable of causing lung disease. Our aim is to find disease-controlling molecules that could be blocked with new drugs that would suppress disease but spare defenses against lung infections.Read moreRead less
The Role Of Src Family Tyrosine Kinases In Inflammatory Lung Disease And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$535,333.00
Summary
We aim to learn why some people develop COPD, a serious lung disease, and adenocarcinoma, a common fatal lung cancer. COPD is mostly caused by cigarette smoke which induces lung inflammation. Lung inflammation, which involves macrophage activation, is a major cancer risk. Macrophages can destroy lung tissue, and they may promote cancer development. We will study the role of Src kinases, which can regulate macrophage activation, which may lead to new treatments for these diseases.
Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown cause which is unresponsive to current therapy. This study builds on recent work by this group highlighting the importance of a cell signalling molecule called STAT3 in the development of this disease. In particular, two cell types that utilise STAT3 signalling, epithelial cells and B cells, will be examined to see if blocking their STAT3 responses could be a novel therapeutic approach.
In the asthmatic lung structural changes, such as increased deposition of proteins which form the scaffolding of the airways (the extracellular matrix proteins), and an increased mass of bronchial smooth muscle cells occur. Many of these critical structural changes are not reversed or prevented with current asthma therapy, thus we need to investigate, by using lung cells and tissues , why they happen and how we can prevent them.