Functional Characterisation Of Novel Metabolites In Asthma And Identification Of New Biomarkers
Funder
National Health and Medical Research Council
Funding Amount
$829,922.00
Summary
Asthma is a chronic inflammatory disease of the airways that represents a major health burden. Severe asthma represents 10% of those suffering the disease and poses an urgent problem due to exacerbations and resistance to current therapies. We have conducted the first study of the metabolites that are altered in the airways of patients with severe asthma and identified functional metabolites and disease biomarkers. We now aim to assess the function of these molecules in asthma disease models.
Microtubule Capture By E-cadherin: A Novel Mechanism For Dynamic Cell-cell Adhesion.
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
This project studies the molecular mechanisms responsible for holding cells together in normal tissues. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside at the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, adhere to one another. By this means populations of individual cells can be linked together into cohesive populations (i.e. the tissues or organs of the body). The importance of cadherin adhesion is exemplified ....This project studies the molecular mechanisms responsible for holding cells together in normal tissues. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside at the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, adhere to one another. By this means populations of individual cells can be linked together into cohesive populations (i.e. the tissues or organs of the body). The importance of cadherin adhesion is exemplified by the well-documented observation that disruption of cadherin adhesion contributes to many important diseases, including inflammation of epithelia and cancers. Thus understanding the mechanisms by which cadherins hold cells together is necessary for us to understand the molecular basis of commondisease. It has long been known that cadherins work in cooperation with elements within the cell, called the cytoskeleton. My lab has recently made the novel discovery that microtubules, specific components of the cytoskeleton, can regulate the functionof cadherin adhesion molecules. Inparticular, microtubules appear to affect how cadherins can participate in dynamic cell processes necessary for cells to be properly organized in tissues. In this project we will probe the molecular mechanisms responsible for this effect of microtubules. The information obtained will provide important new insights into how dynamic cadherin adhesion is controlled, to help our understanding of the cellular mechanisms that couple cells into tissues, and how they may be disrupted in diesase.Read moreRead less
Preserving Junctions: Regulating Cadherins By Rho And Myosin 2.
Funder
National Health and Medical Research Council
Funding Amount
$425,500.00
Summary
This project studies the molecular mechanisms responsible for holding cells together in normal tissues. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside at the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, adhere to one another. By this means populations of individual cells can be linked together into cohesive populations (i.e. the tissues or organs of the body). The importance of cadherin adhesion is exemplified ....This project studies the molecular mechanisms responsible for holding cells together in normal tissues. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside at the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, adhere to one another. By this means populations of individual cells can be linked together into cohesive populations (i.e. the tissues or organs of the body). The importance of cadherin adhesion is exemplified by the well-documented observation that disruption of cadherin adhesion contributes to many important diseases, including inflammation of epithelia and cancers. Thus understanding the mechanisms by which cadherins hold cells together is necessary for us to understand the molecular basis of commondisease. Characteristically, cadherins accumulate in structures called adherens junctions, and preserving those junctions is important both for tissues to organize and also to prevent tumor progression. Despite this, we know very little about how junctions are preserved in epithelia. The research to be conducted in this grant will examine exactly this problem. It builds upon recent findings from my lab which indicate that the motor molecule, myosin 2 plays an essential role in preserving junctions. Furthermore, we will test the role for signaling pathways within cells to control the activity of myosin 2 at junctions. This research will provide important novel insights into the cellular mechanisms that couple cells into tissues, and how they may be disrupted in diesase.Read moreRead less
Epithelial Drivers Of Neutrophil Plasticity In Early Cystic Fibrosis Lung Disease
Funder
National Health and Medical Research Council
Funding Amount
$849,462.00
Summary
Why airway inflammation becomes chronic so early in life for people with cystic fibrosis (CF) is unclear. This project will use the latest techniques to characterise immune cells found in airways of infants with CF and model in the laboratory how immune cells react to the CF airway. We will challenge CF airway cells with different bugs that can infect the lung, then see if the responses by CF airway cells can change the normal response of immune cells, triggering chronic disease.
Interferon Regulatory Factor 6: A Novel Epithelial-specific Regulator Of Mucosal Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$517,989.00
Summary
Epithelial cells lining the respiratory and gastrointestinal tracts play pivotal roles in protecting us from infection. Inflammatory factors released by epithelial cells are important for fighting infection; however, they also contribute to chronic inflammatory diseases. We aim to understand how a protein called IRF6 regulates the inflammatory response of epithelial cells. The knowledge gained will identify new therapeutic approaches for inflammatory diseases.
Role Of Amnion Derived Stem Cells In Reducing Lung Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$349,485.00
Summary
Human amniotic epithelial multipotential cells from the term placenta are being studied in a mouse model of pulmonary fibrosis-emphysema to demonstrate their anti-inflammatory, anti-fibrotic, immune-suppresive and lung repair capability. The availability and numbers of these cells from discarded placentas at birth are unlimited and their potential to repair serious lung disease would have strong clinical interest as a new stem cell therapy.
Epithelium-fibroblast Interactions In Response To Allergic Airway Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$235,526.00
Summary
The airways of an asthmatic patient undergo dramatic structural changes over time. This remodelling is thought to be responsible for producing the changes in lung function that are frequently observed in someone with the disease. However, in contrast to normal wound repair, it is unclear why in the majority of asthmatics, inflammation leads to ongoing remodelling rather than a self limiting healing process. In this context, cells that line the airways (epithelium) as well as cells that sit immed ....The airways of an asthmatic patient undergo dramatic structural changes over time. This remodelling is thought to be responsible for producing the changes in lung function that are frequently observed in someone with the disease. However, in contrast to normal wound repair, it is unclear why in the majority of asthmatics, inflammation leads to ongoing remodelling rather than a self limiting healing process. In this context, cells that line the airways (epithelium) as well as cells that sit immediately beneath them (fibroblasts) are important sources of mediators and structural matrix proteins that contribute to these processes. Under normal conditions, signals from these structural proteins are transmitted to the cells via specific adhesion molecules. However, in asthma epithelial cells are frequently damaged and detached, and fibroblasts appear to proliferate and undergo changes in their appearance. This projects aims to investigate the expression and function of specific cell adhesion molecules in the epithelium and fibroblasts following airway inflammation. Specifically, this proposal aims to determine which adhesion molecules are associated with upregulated proliferation and production of matrix proteins. We will also examine the effects of two novel mediators, thought to play a role in remodelling on the expression and function of these adhesion molecules. Proliferation of these cells and the altered deposition of matrix proteins may be a key feature of airway wall thickening and hyperreactivity that is a characteristic feature of asthma. The balance of deposition and breakdown of matrix proteins is regulated by a variety of mediators. Defining what regulates the expression and activity of adhesion molecules is of fundamental importance in determining how the normal repair processes may evolve into airway wall remodelling.Read moreRead less
It has recently become apparent that we all make a substance in the lungs called nitric oxide. The amount that we make is increased in diseases such as allergic asthma. This project will study the connection between the allergen being inhaled and the excess nitric oxide being made by cells in the lung. From this research we will have a better understanding of the processess involved and develop better therapies for asthma.
Recycling Endosomes Governing Cell Polarity And Cytokine Secretion.
Funder
National Health and Medical Research Council
Funding Amount
$958,412.00
Summary
Cytokines are chemical messengers released by cells to mount inflammatory responses to fight infections. The timing and direction of cytokine release must be tightly regulated. We investigate the cellular compartments and molecules that control cytokine secretion using sophisticated live cell imaging. Uncontrolled cytokine release is the main cause of ongoing inflammation in arthritis and inflammatory bowel disease and our studies aim to identify cellular targets for new drug development.
This work will analyse how cells, the building blocks of tissues, are organized together to form functioning organs. It focuses on the adhesion molecules that allow cells to recognize one another, which cooperate with the internal skeleton of cells to link them together. We aim to understand how these cellular systems work normally and how they are targeted to disrupt tissue integrity in diseases like cancer and inflammation.