THE ROLE OFPROTEASES AND PROTEASE ACTIVATED RECEPTORS IN RESPIRATORY EPITHELIAL CELL FUNCTION IN ASTHMA
Funder
National Health and Medical Research Council
Funding Amount
$457,500.00
Summary
The epithelium lines the airways and is, therefore, constantly exposed to a variety of exogenous antigens, infectious agents and noxious stimuli. This tissue responds to such stimuli by secreting substances that help counteract the insult while simultaneously initiating healing and repair. In this proposal, we will investigate the role of a group of receptors present on the surface of the epithelium which monitor the area surrounding the epithelium for the presence of enzymes which digest host t ....The epithelium lines the airways and is, therefore, constantly exposed to a variety of exogenous antigens, infectious agents and noxious stimuli. This tissue responds to such stimuli by secreting substances that help counteract the insult while simultaneously initiating healing and repair. In this proposal, we will investigate the role of a group of receptors present on the surface of the epithelium which monitor the area surrounding the epithelium for the presence of enzymes which digest host tissue or pathogens. These receptors, known as PAR, sense their suroundings by binding the protease, a process which then triggers the cell to respond in an appropriate way by releasing cytokines and mediators. There are 4 PAR, each with different properties, and are present on many cells of the body. However, little information about their role on epithelium exists. Although we have shown them to be upregulated in the epithelium in the socio-economically important disease, asthma, their function in this disease remains elusive. We will, therefore, initiate studies to define their role in inflammation, healing and repair as this information may lead to a better understanding of their role in disease which may then translate into better treatment.Read moreRead less
Alzheimer’s disease is a progressive brain disease which is results in memory loss and brain cell death. All currently prescribed drugs treat the memory loss but are unable to stop the deterioration of brain cells. We have previously developed a class of drugs that reverse memory loss targeting – these drugs target a protein called IRAP. We recently found that these drugs also reduce the disease pathology. This research proposal aims to investigate the role of IRAP in the initiation or progressi ....Alzheimer’s disease is a progressive brain disease which is results in memory loss and brain cell death. All currently prescribed drugs treat the memory loss but are unable to stop the deterioration of brain cells. We have previously developed a class of drugs that reverse memory loss targeting – these drugs target a protein called IRAP. We recently found that these drugs also reduce the disease pathology. This research proposal aims to investigate the role of IRAP in the initiation or progression of Alzheimer’s disease pathology.Read moreRead less
PROTEASE ACTIVATED RECEPTORS PRESENT ON TYPE II PNEUMOCYTES PLAY AN IMPORTANT ROLE IN PULMONARY SURFACTANT PRODUCTION
Funder
National Health and Medical Research Council
Funding Amount
$562,427.00
Summary
Lung surfactant comprises both lipids and proteins and is secreted by alveolar type II cells into the liquid lining the air-tissue interface. These monolayers stabilise the alveoli, decrease the work of breathing, prevent oedema, and assist in the clearance of foreign particles from the epithelial lining. In addition to this homeostatic role in respiration, there is evidence linking surfactant with removal of harmful microbes and allergy and asthma. Various stimuli are known to control surfactan ....Lung surfactant comprises both lipids and proteins and is secreted by alveolar type II cells into the liquid lining the air-tissue interface. These monolayers stabilise the alveoli, decrease the work of breathing, prevent oedema, and assist in the clearance of foreign particles from the epithelial lining. In addition to this homeostatic role in respiration, there is evidence linking surfactant with removal of harmful microbes and allergy and asthma. Various stimuli are known to control surfactant production to maintain normal, healthy lung function but with microbes and allergen, where inflammation is common, the role of pro-inflammatory proteases and protease activated receptors (PAR) in their biology has not been investigated. Our preliminary findings now show, however, that they are involved. In this proposal, we will determine their importance in surfactant production both in vitro and in vivo. The possibility that proteases and their receptors play a role in surfactant production has not been previously described but if shown to play a role in production, we will have identified a novel pathway that will aid our understanding of the mechanisms of surfactant release and, possibly, lung development. Thus, it is anticipated that results from this study may contribute to a significant reduction in morbidity associated with the above mentioned diseases, resulting in reduction in the cost of health care. Social benefits obtained from study this would be improved health as a result of the application of the findings to patients who currently lead a life heavy dependant on medical interventions.Read moreRead less
Roles Of Enzymes Of The Dipeptidyl Peptidase Gene Family In Human Liver
Funder
National Health and Medical Research Council
Funding Amount
$79,750.00
Summary
Chronic liver diseases, particularly those caused by autoimmune disease, alcohol and Hepatitis B and C virus infection, are major causes of morbidity and mortality in our community. They are characterised by progressive scarring of the liver which finally leads to liver failure and the need in many cases for organ transplantation. Each year 15,000 Australians become infected, probably for life, with hepatitis C virus. Unless more effective treatments are developed approximately 20% of these infe ....Chronic liver diseases, particularly those caused by autoimmune disease, alcohol and Hepatitis B and C virus infection, are major causes of morbidity and mortality in our community. They are characterised by progressive scarring of the liver which finally leads to liver failure and the need in many cases for organ transplantation. Each year 15,000 Australians become infected, probably for life, with hepatitis C virus. Unless more effective treatments are developed approximately 20% of these infections will progress to liver failure or liver cancer within 30 years. Diabetes afflicts 150 million people, and 90% have Type 2 diabetes. We request funding of our research on a family of enzymes highly prospective as targets for novel therapies for these diseases. We are internationally recognised experts on this enzyme family and on liver disease. The prototype member of this enzyme family, dipeptidyl peptidase (DP) IV, is being targeted by novel drugs that are in phase III clinical trials for Type 2 diabetes. Family member fibroblast activation protein (FAP) is targeted by novel anti-cancer drugs We were first to clone and lodge patent applications for two new enzymes of this family, DP8 and DP9. Our research proposal would lead to determination of whether FAP, DP8 and-or DP9 are valuable targets for novel liver disease therapeutics and facilitate generating the development of such therapeutics by a more thorough understanding of the activities and roles of these enzymes Completion of this project will greatly increase our understanding of these enzymes and their roles in chronic liver injury. This work can potentially lead to the development of specific inhibitors of enzyme function designed to relieve liver damage.Read moreRead less
The Role Of Fibroblast Activation Protein In Chronic Liver Injury
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
Chronic liver diseases, particularly those caused by Hepatitis B virus and Hepatitis C virus infection, are major causes of morbidity and mortality in our community. They are characterised by progressive scarring of the liver which finally leads to liver failure and the need in many cases for organ transplantation. We have identified a key molecule Fibroblast Activation Protein (FAP) that may play a key role and the process of liver fibrosis (scarring). The aims of the project are four fold: (1) ....Chronic liver diseases, particularly those caused by Hepatitis B virus and Hepatitis C virus infection, are major causes of morbidity and mortality in our community. They are characterised by progressive scarring of the liver which finally leads to liver failure and the need in many cases for organ transplantation. We have identified a key molecule Fibroblast Activation Protein (FAP) that may play a key role and the process of liver fibrosis (scarring). The aims of the project are four fold: (1) To characterise where and on what cells FAP is produced in the liver and whether FAP levels correlate with the development of fibrosis in human chronic liver diseases caused by either Hepatitis B or Hepatitis C virus infections. (2) To examine a mouse strain in which the FAP molecule is knocked out ie absent. This will tell us whether FAP itself is essential for the development of fibrosis. (3) To isolate the cells within the liver that make FAP and to examine how particular functions of these cells are modified by FAP. (4) To find out what particular molecules FAP acts upon to perform its functions. The achievement of these aims will greatly increase our understanding of this key enzyme and its role in chronic liver injury. This work can potentially lead to the development of specific inhibitors of FAP function designed to relieve liver damage.Read moreRead less