Actions Of Vanilloids In The Nucleus Of The Solitary Tract
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
Capsaicin, the active ingredient of hot chillies, and other pungent plant extracts have been used for millennia to relieve minor pain. We now know that these agents produce pain relief (analgesia) by numbing the very nerve cells (neurons) which transmit pain signals to the brain. The unique analgesic properties of vanilloids may have a place in modern medicine, giving relief to sufferers of certain types of chronic pain (e.g., neuropathic pain) which are not responsive to morphine-like analgesic ....Capsaicin, the active ingredient of hot chillies, and other pungent plant extracts have been used for millennia to relieve minor pain. We now know that these agents produce pain relief (analgesia) by numbing the very nerve cells (neurons) which transmit pain signals to the brain. The unique analgesic properties of vanilloids may have a place in modern medicine, giving relief to sufferers of certain types of chronic pain (e.g., neuropathic pain) which are not responsive to morphine-like analgesics. Indeed, the promise of more potent and less pungent vanilloid analgesics has led to the discovery of numerous naturally-occurring and synthetic vanilloids. However, although the neurons which convey information regarding blood pressure and the oxygen content of arterial blood to control centres in the brain stem are also stimulated by vanilloids, the central (brain stem) actions of vanilloids on blood pressure and respiration have not been investigated in detail. Thus, the aim of this project is to describe the characteristics of vanilloid receptors in the brain stem, determine the acute and chronic effects of naturally-occurring and synthetic vanilloids on blood pressure and respiration, and elucidate the role played by other neurotransmitter chemicals in the actions of vanilloids. The results of these studies will have major implications in the future use of vanilloids as analgesics.Read moreRead less
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
Airway Smooth Muscle Contribution To Remodelling In Asthma.
Funder
National Health and Medical Research Council
Funding Amount
$211,320.00
Summary
Asthma is an airway disease that affects more than 10% of adults and 25% of children in Australia and in 1998 caused 675 deaths. The cost to the community is in excess of $720 million a year. The abnormality in asthma is not fully understood, however inflammation, changes to the structure of the airways and excessive airway narrowing are key factors. Inflammation and the allergic reactions which accompany asthma cause fluid to leak from tiny blood vessels in the lung. This fluid and the inflamma ....Asthma is an airway disease that affects more than 10% of adults and 25% of children in Australia and in 1998 caused 675 deaths. The cost to the community is in excess of $720 million a year. The abnormality in asthma is not fully understood, however inflammation, changes to the structure of the airways and excessive airway narrowing are key factors. Inflammation and the allergic reactions which accompany asthma cause fluid to leak from tiny blood vessels in the lung. This fluid and the inflammation are linked to changes in the airway which include structural protein deposition - breakdown and an overgrowth of the smooth muscle that lines the walls of the airway. Our work is focussed on understanding the relationship between the structural protein deposition - breakdown and excess muscle growth. We also hope to gain a better understanding of the way asthma treatments combat these changes in the asthmatic airways.Read moreRead less
Mechanisms Of Protease-activated Receptor-2-mediated Bronchoprotection
Funder
National Health and Medical Research Council
Funding Amount
$354,758.00
Summary
The incidence of asthma continues to increase globally, yet there have been few real therapeutic advances. Our research, however, has recently uncovered a novel mechanism that protects the airways from inflammatory diseases like asthma. We have found that the layer of cells that line the airways - the epithelium - acts as a detector of early inflammatory events and releases anti-inflammatory substances. The lungs achieve this level of protection via 'sensor' molecules called receptors which are ....The incidence of asthma continues to increase globally, yet there have been few real therapeutic advances. Our research, however, has recently uncovered a novel mechanism that protects the airways from inflammatory diseases like asthma. We have found that the layer of cells that line the airways - the epithelium - acts as a detector of early inflammatory events and releases anti-inflammatory substances. The lungs achieve this level of protection via 'sensor' molecules called receptors which are located in the epithelium. In the case of our discovery, these receptors are called protease-activated receptors (PARs) to highlight the unique manner in which they are turned on or activated by enzymes called proteases. We have discovered that the epithelium of the lungs stores these enzymes and probably releases them during the inital stages of infection. Once released, these enzymes are detected by PARs on epithelial cells which then release substances that inhibit multiple inflammatory pathways. This mechanism protects the airways from effects that make breathing difficult, as in asthma. We have confirmed that this system provides protection in the airways of intact animals. The purpose of this projects outlined in this application is to examine the effects of activating one PAR, PAR2, on several processes in the lung, in order to characterise the individual events and processes that underlie the protective response. These studies will enable us to determine whether synthetic compounds that activate PAR2 are potential novel compounds for the treatment of diseases like asthma.Read moreRead less
MECHANISMS OF CEREBROVASCULAR REGULATION IN HEALTH AND DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$216,430.00
Summary
Failure of the cerebral circulation to meet the brain's immediate high nutritive requirements results in stroke in just a few minutes. Stroke continues to be a major cause of death and disability, and this major medical challenge requires urgent and significant research at the basic level to better understand mechanisms of normal, and then abnormal, regulation of cerebral artery function. The project will examine the importance of a novel mechanism in regulating brain blood flow by affecting the ....Failure of the cerebral circulation to meet the brain's immediate high nutritive requirements results in stroke in just a few minutes. Stroke continues to be a major cause of death and disability, and this major medical challenge requires urgent and significant research at the basic level to better understand mechanisms of normal, and then abnormal, regulation of cerebral artery function. The project will examine the importance of a novel mechanism in regulating brain blood flow by affecting the degree of opening of the cerebral arteries. This mechanism involves activation of an enzyme, Rho-kinase, which is present in the wall of blood vessels. The applicants believe that this process plays an important role in the normal, healthy regulation of blood supply to the brain. Moreover, there are strong reasons for us to speculate that the function of this enzyme is abnormally high in two disease states that are associated with an increased risk of stroke - high blood pressure and subarachnoid haemorrhage. We will employ a variety of techniques to assess the importance of Rho-kinase in cerebral artery function in the living body, and also in isolated segments of artery. The results are expected to provide major new insight into mechanisms that regulate brain blood flow, and the knowledge gained here may lead to better therapies to prevent or treat stroke.Read moreRead less
Does NADPH Oxidase Link Gender, Hormone Replacement Therapy And Outcome After Stroke?
Funder
National Health and Medical Research Council
Funding Amount
$481,439.00
Summary
This project will assess whether the reduction of a novel mechanism to open brain arteries (i.e. via activation of 'Nox' proteins and generation of oxygen radicals) is a possible explanation of why hormone replacement therapy (HRT) increases the risk of stroke in postmenopausal women. We will compare brain artery function of normal mice with those deficient in certain Nox genes in models of menopause, HRT and stroke. This knowledge should lead to safer stroke therapies in women and men.
Airway Virus Infection, Protease-activated Receptors And Microvascular Permeability
Funder
National Health and Medical Research Council
Funding Amount
$421,527.00
Summary
Asthma is an inflammatory airway disease which kills about 800 Australians each year and otherwise afflicts millions of children and adults in all age groups. Respiratory tract viral infections trigger inflammation and asthma. We believe that this is caused by the loss of naturally protective, bronchodilator and anti-inflammatory substances such as prostaglandin E2 and increased production of asthma promoting substances such as endothelins. Both of these substances are made by the epithelial lin ....Asthma is an inflammatory airway disease which kills about 800 Australians each year and otherwise afflicts millions of children and adults in all age groups. Respiratory tract viral infections trigger inflammation and asthma. We believe that this is caused by the loss of naturally protective, bronchodilator and anti-inflammatory substances such as prostaglandin E2 and increased production of asthma promoting substances such as endothelins. Both of these substances are made by the epithelial lining cells of the bronchi where viruses grow. This project will assess the influence of respiratory tract virus infection on epithelial mechanisms for the production of PGE2 and endothelins. Respiratory viral infections are accompanied by airway inflammation and thus by elevated microvascular permeability and oedema which exacerbates obstruction in asthma. We will measure airway microvascular permeability changes during viral infection and assess the protective effect of stimulating protease-activated receptors which increases PGE2 production. The impact of the PAR system on the integrity of microvascular tissue and on epithelial endothelin production has not been previously investigated. In addition, the influence of respiratory tract viral infection on PAR function in this system is also unknown, but is potentially of great importance to our understanding of the behaviour and regulation of this natural bronchoprotective pathway. This work may lead to the use of novel PAR activators as combined bronchodilator-anti-inflammatory therapies in asthma.Read moreRead less