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
Effect Of Prostaglandin E2 On The Periodontium And Alveolar Bone Formation
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
Dental disease affecting the supporting structures of teeth (the periodontium), is prevalent in our society. Periodontal disease results in destruction of bone around teeth, loosening of teeth, compromised chewing function, and tooth loss. Over the last twenty years reports into the effects of prostaglandin E2 (PGE2) on the skeleton have been divided and controversial. While historically PGE2 has been reported to promote bone resorption, more recently it has been demonstrated that when PGE is pl ....Dental disease affecting the supporting structures of teeth (the periodontium), is prevalent in our society. Periodontal disease results in destruction of bone around teeth, loosening of teeth, compromised chewing function, and tooth loss. Over the last twenty years reports into the effects of prostaglandin E2 (PGE2) on the skeleton have been divided and controversial. While historically PGE2 has been reported to promote bone resorption, more recently it has been demonstrated that when PGE is placed in contact with mandibular bone, adjacent to erupted teeth, new bone and cementum formation occurs. The ability of PGE2 to induce new bone formation indicates a potential use for PGE2 in the management of bone loss associated with periodontal diseases, and the formation of new bone around dental implants, and around teeth following orthodontic movement. Growth factors are active in healing and have valuable applications in augmenting wound repair. Osseous and dental tissues are rich in growth factors, and these factors are involved with the regulation of bone metabolism as well as tissue repair, thus the action of PGE2 on the periodontium is most likely regulated via these factors. Since regeneration of the periodontium is a fundamental goal of dentistry, any treatment which leads to predictable formation of new connective tissues and their long term stability would be a major clinical advance.Read moreRead less
Self-limiting Anti-inflammatory Actions Of Glucocorticoids In Asthma
Funder
National Health and Medical Research Council
Funding Amount
$377,036.00
Summary
Asthma is a disease characterised by excessive narrowing of the airway tubes resulting in difficulty exhaling air from the lungs. Symptoms of asthma include coughing, wheezing, shortness of breath and difficulty in breathing. Asthma affects almost 1 in 5 Australians and is especially prevelant in children. One in every three Australians will suffer from symptoms of asthma at some time in their life and despite current therapy, asthma is responsible for the deaths of more than 700 Australians eve ....Asthma is a disease characterised by excessive narrowing of the airway tubes resulting in difficulty exhaling air from the lungs. Symptoms of asthma include coughing, wheezing, shortness of breath and difficulty in breathing. Asthma affects almost 1 in 5 Australians and is especially prevelant in children. One in every three Australians will suffer from symptoms of asthma at some time in their life and despite current therapy, asthma is responsible for the deaths of more than 700 Australians every year. Airway tubes of asthmatics have more and larger contractile muscle cells lining the tubes. This increase in muscle mass results from chemicals that are released from white blood cells that migrate into the airway tubes during and after asthma attacks. This thickening slows airflow through the airway tubes because the muscle mass bulges into the holes of the tubes and when the muscle shortens the total diameter of the tubes decrease. We have recently shown that steroids used by asthmatics to treat the white blood cell contribution to the disease can reduce the growth of airway muscle. However, when the muscle has been pretreated with factors that are present in the inflamed airway, the anti-growth effects of steroids are prevented. This effect of the steroids is due to reduced production of a substance called prostaglandin E2 which can also reduce the growth of muscle. Thus, whilst steroids may help in treating some of the symptoms of asthma, they may be suboptimal in the treatment of muscle thickening and other aspects of the disease which involve cell division and multiplication. Our specific question in the next phase of this research is whether steroid inhibition of the release of prostaglandins compromises the useful actions of steroids on the growth of the airway tubes. The findings of this proposed study will provide new information on the role of steroids in asthma and may lead to better therapeutic strategies for the treatment of severe asthma.Read moreRead less