Protease-activated Receptors As Potential Drug Targets In Allergic Airways Disease
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
Asthma is a lung disease that kills about 700 Australians each year and causes widespread morbidity in our community. For people with allergic asthma inhalation of allergens such as those contained in house dust triggers an immune response that causes swelling of the airway wall, overproduction of mucus and bronchial smooth muscle contraction. These effects lead to the narrowing of the airways that makes breathing more difficult in people with asthma. Our research groups have been investigating ....Asthma is a lung disease that kills about 700 Australians each year and causes widespread morbidity in our community. For people with allergic asthma inhalation of allergens such as those contained in house dust triggers an immune response that causes swelling of the airway wall, overproduction of mucus and bronchial smooth muscle contraction. These effects lead to the narrowing of the airways that makes breathing more difficult in people with asthma. Our research groups have been investigating a novel group of proteins, called protease-activated receptors (PARs), and in an exciting development have found that substances that stimulate PARs inhibit allergic airways inflammation in mice, which is a well-established animal model of allergic asthma. This raises the possibility that PAR stimulants may in the future be developed as anti-asthma drugs. However, there are many large gaps in our understanding of airway PARs that need to be filled before their use as anti-asthma drugs can be contemplated. Thus, the current study will address many important questions: Do PAR stimulants always improve allergic inflammation, or are there some doses or times of dosing that worsen allergic inflammation? Stimulants of one PAR, called PAR2, improve allergic inflammation, but what about stimulants of the three other PARs (PAR1, PAR3 and PAR4) that exist in the airways? How do PARs improve allergic inflammation, and which substances and cells are involved? Are PAR stimulants also effective in more complex animal models of allergic inflammation, such as those involving proteolytic allergens (e.g. Der p1 from the house dust mite), respiratory tract viruses, and extended periods of allergen exposure (chronic models) that better reflect the human disease allergic asthma? The answers to these and a range of other questions will significantly improve our understanding of the potential utility of PAR stimulants in the treatment of allergic airways disease.Read moreRead less
How Anti-inflammatory Drugs Differentially Affect The Bronchoprotective Signalling Of Protease-Activated Receptor-2
Funder
National Health and Medical Research Council
Funding Amount
$421,690.00
Summary
Asthma contributes significantly to the burden of ill health and impaired quality of life in Australian communities, and for many measures of asthma, Australia has amongst the highest prevalence when compared with other countries. Furthermore, there is evidence that the prevalence of asthma has increased during the latter part of the 20th century. There is currently no cure for asthma, and the need for better asthma therapies through the discovery of novel targets for drug development has never ....Asthma contributes significantly to the burden of ill health and impaired quality of life in Australian communities, and for many measures of asthma, Australia has amongst the highest prevalence when compared with other countries. Furthermore, there is evidence that the prevalence of asthma has increased during the latter part of the 20th century. There is currently no cure for asthma, and the need for better asthma therapies through the discovery of novel targets for drug development has never been more acute. PAR2 is a receptor that is located on the surface of many cell types in the respiratory tract, including the epithelial cells that line the airway tubes. When PAR2 is stimulated it causes the epithelial cells to produce and release large amounts of PGE2 (prostaglandin E2). PGE2 released from epithelial cells then binds to other proteins such as the prostanoid EP2 receptor located on smooth muscle cells. This causes the airway smooth muscle cells to relax. Drugs that cause airway smooth muscle cells to relax - called bronchodilators - make breathing easier, and are often used during an asthma attack to relieve bronchoconstriction. It also appears that activation of the PPP axis inhibits airway wall swelling (that is, has anti-inflammatory actions). Thus, drugs that activate the PPP axis may be beneficial in the treatment of asthma by reducing airway sweeling and producing smooth muscle relaxation. Thus, we we are investigating ways of optimally stimulating the PAR2-PGE2-prostanoid EP2 receptor axis (the PPP axis), as a means of develeping novel treatments for asthma.Read moreRead less
Treating tuberculosis: targeted delivery of multidrug nano-suspensions. Tuberculosis (TB) is a lung disease of worldwide prevalence. Treatment times are long and mortality is high in children and the elderly. Current treatments are ineffective and drug resistant TB is a real pandemic threat. The project will develop a cost-effective nano-particle system that can be incorporated into conventional nebulisers for use worldwide.
Understanding Cell Signalling Mechanisms Activated By Relaxin Family Peptides: Targets With Therapeutic Potential
Funder
National Health and Medical Research Council
Funding Amount
$306,842.00
Summary
One of the most powerful ways that the activity of the cells that make up the tissues and organs of the body can be changed is by the interaction of chemicals with proteins called receptors located at the cell surface. The commonest type of receptor is called a G-protein coupled receptor as it is linked to mechanisms inside the cell by the G-proteins. These receptors are the most commonly targeted by pharmaceutical companies that wish to alter the responses of cells for therapeutic purposes and ....One of the most powerful ways that the activity of the cells that make up the tissues and organs of the body can be changed is by the interaction of chemicals with proteins called receptors located at the cell surface. The commonest type of receptor is called a G-protein coupled receptor as it is linked to mechanisms inside the cell by the G-proteins. These receptors are the most commonly targeted by pharmaceutical companies that wish to alter the responses of cells for therapeutic purposes and almost 2-3 of all drugs currently marketed work through these proteins. This project will examine the mechanisms whereby certain types of G-protein coupled receptor produce signals in cells and determine what are the critical areas of the receptor for these interactions. The receptors involved have been discovered only in the last 4 years and little is known of the ways these change the activity of cells. The substances acting on these receptors have potential for development as targets for drugs that have the potential to treat fibrosis which is a feature of many diseases including cardiac failure, kidney failure and lung disease.Read moreRead less
Understanding the biology of reactive oxygen species. This project will utilise forefront technologies to identify and characterise fundamental biological processes involving toxic free radicals that cause infectious disease and cancer. The approach synergises with researchers across disciplines and universities to ultimately identify future drugs to improve and maintain health.
Advanced nanotechnologies for targeting biofilms. Advanced nanotechnologies for targeting biofilms. This project aims to develop nano-particulate systems based on a single platform technology that can be delivered as an aerosol. The current lack of a suitable formulation and delivery system hinders the eradication of fungal and bacterial biofilms from surfaces. These new systems will have enhanced residency time, penetration properties and effectiveness in biofilms. This project intends to under ....Advanced nanotechnologies for targeting biofilms. Advanced nanotechnologies for targeting biofilms. This project aims to develop nano-particulate systems based on a single platform technology that can be delivered as an aerosol. The current lack of a suitable formulation and delivery system hinders the eradication of fungal and bacterial biofilms from surfaces. These new systems will have enhanced residency time, penetration properties and effectiveness in biofilms. This project intends to understand the properties that govern the formation and interactions in these systems, and develop in-vitro tools that the wider scientific community can use. The project expects to generate a single platform that can be used for the eradication of biofilms in numerous applications, from healthcare to agriculture.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0668493
Funder
Australian Research Council
Funding Amount
$230,000.00
Summary
Characterising particulate laden flow in the lung airways: from drug delivery to primary anthropogenic sources. Facilities will provide infrastructure at Monash University and University of Sydney to continue the collaboration enhancing excellence in an exciting application of fluidics research, supporting the highest level of graduate training, providing innovative tools for industry and promoting industrial collaborations. The infrastructure is unique and will create international funding and ....Characterising particulate laden flow in the lung airways: from drug delivery to primary anthropogenic sources. Facilities will provide infrastructure at Monash University and University of Sydney to continue the collaboration enhancing excellence in an exciting application of fluidics research, supporting the highest level of graduate training, providing innovative tools for industry and promoting industrial collaborations. The infrastructure is unique and will create international funding and collaborative opportunities to support research and postgraduate training. The equipment will add value to existing infrastructure to enhance understanding of particulate flow with the paradoxical outcomes of improving drug deposition in respiratory delivery and of minimising anthropogenic particular deposition for better therapeutic and health outcomes.Read moreRead less
Design And Use Of Human Hematopoietic Prostaglandin D2 Synthase Inhibitors In Allergic Asthma And Bone Diseases
Funder
National Health and Medical Research Council
Funding Amount
$517,960.00
Summary
Many currently used non-steroidal anti-inflammatory drugs are burdened by side effects such as gastrointestinal bleeding or increased risk of heart attack. This is because they ablate the production of a class of molecules called prostaglandins. We believe it is possible to fine tune the action of these drugs and reduce the side effect risk. There is evidence to suggest that only some prostaglandins are involved in inflammation, so the risk of side effect can be reduced by blocking the productio ....Many currently used non-steroidal anti-inflammatory drugs are burdened by side effects such as gastrointestinal bleeding or increased risk of heart attack. This is because they ablate the production of a class of molecules called prostaglandins. We believe it is possible to fine tune the action of these drugs and reduce the side effect risk. There is evidence to suggest that only some prostaglandins are involved in inflammation, so the risk of side effect can be reduced by blocking the production of only a small set. One prostaglandin, prostaglandin D2, is known to cause many characteristics of allergic asthma and may also contribute to osteoarthritis, although the evidence for this is contradictory. We will determine any therapeutic benefit to blocking the production of prostaglandin D2 in these diseases by developing compounds that only inhibit the enzyme responsible for its production.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0560661
Funder
Australian Research Council
Funding Amount
$245,300.00
Summary
Particulate Characterisation for Pharmaceutical and Engineering Applications. The aim of this proposal is to establish joint facilities between the University of Sydney, Monash University and UNSW for the characterization of surface properties and particle sizes of pharmaceutical aerosols and industrial powders. Such knowledge is important for controlling aerosol production and delivery of drug particles to the lungs. This will have a significant benefit to the pharmaceutical industry and patien ....Particulate Characterisation for Pharmaceutical and Engineering Applications. The aim of this proposal is to establish joint facilities between the University of Sydney, Monash University and UNSW for the characterization of surface properties and particle sizes of pharmaceutical aerosols and industrial powders. Such knowledge is important for controlling aerosol production and delivery of drug particles to the lungs. This will have a significant benefit to the pharmaceutical industry and patients requiring aerosol treatment. Further, the proposed facilities will enhance research in complex particulate processes and modelling, functional nanomaterials, and soft sensor development, thus keeping Australia at the forefront of powder research into various high value adding particulate areas.Read moreRead less
Ultra-low dose dry powder inhaler technology for the treatment of respiratory diseases. Drug molecules are being developed for respiratory diseases, which are highly potent but beyond our capability in terms of delivery. Using a combination of high-end particle engineering and characterisation approaches, coupled with computational modelling, the project will develop a theoretical model that can be used to deliver ultra-low doses to the lungs.