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
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.
Molecular Interactions Of Novel Conotoxin Inhibitors Of The Noradrenaline Transporter
Funder
National Health and Medical Research Council
Funding Amount
$392,036.00
Summary
A novel class of conotoxins (chi-conotoxins) has been discovered in the venom of an Australian cone snails, Conus marmoreus. Chi-conotoxins are the first peptide inhibitors of the noradrenaline transporter. From binding studies, it appears they act at a new site, remote from the site of action of antidepressants. This project is aimed at understanding how and where this novel class of peptide binds to the transporter. The results of this study are designed to maximise the potential of these pate ....A novel class of conotoxins (chi-conotoxins) has been discovered in the venom of an Australian cone snails, Conus marmoreus. Chi-conotoxins are the first peptide inhibitors of the noradrenaline transporter. From binding studies, it appears they act at a new site, remote from the site of action of antidepressants. This project is aimed at understanding how and where this novel class of peptide binds to the transporter. The results of this study are designed to maximise the potential of these patented peptides to be used as leads to the development of a new class of therapeutic for controlling the adverse effects of inadequate noradrenaline balance.Read moreRead less
Heme-oxidised Soluble Guanylyl Cyclase, A Mechanism-based Target For Vascular Diagnostics And Vasoprotective Therapy
Funder
National Health and Medical Research Council
Funding Amount
$524,456.00
Summary
Nitric oxide is produced in the inner lining of blood vessels and maintains blood flow via binding to a specific protein, sGC. In disease, sGC is defective and can be targeted by a novel group of drugs which are more active in diseased versus normal blood vessels. This project will examine the use of these drugs as markers of cardiovascular disease and in the treatment of high cholesterol and may lead to the development of new diagnostic tools and therapies for vascular complications.
NOVEL CGMP-BASED THERAPIES PREVENT LEFT VENTRICULAR REMODELLING
Funder
National Health and Medical Research Council
Funding Amount
$533,433.00
Summary
Over 300,000 Australians are affected by heart failure. Current drugs for cardiac remodelling (the decline in heart pumping function and changed structure that precede heart failure) slow but not reverse disease progression. We have identified a new, nitrovasodilator-based therapy superior to those currently available. We propose it represents a more effective treatment for reversing abnormalities in both structure and function in the remodelled heart, preventing or delaying heart failure.
Voltage Dependent Calcium Channels And Vascular Function: Do Microdomains Determine Function?
Funder
National Health and Medical Research Council
Funding Amount
$597,682.00
Summary
Blood flow depends on arterial diameter which can change with contraction of muscle in the vessel wall. Calcium influx through one type of channel in the muscle cells has been considered critical, but drugs targeting these channels have not succeeded in treating the arterial spasm which occurs after stroke and head injury. Our study will investigate the existence and role of other calcium channels in brain arteries. Knowledge gained will likely lead to development of new drug targets for stroke.
TARGETING ROS-INDUCED DAMAGE RESCUES THE DIABETIC HEART
Funder
National Health and Medical Research Council
Funding Amount
$487,669.00
Summary
Over 1 million Australians have diabetes. Many of these patients die from cardiovascular disease. We have identified free radicals as a major cause of decreased pumping function and impaired recovery from each heartbeat in the diabetic heart. Stronger antioxidant approaches and-or activation of protective protein pathways is a more effective treatment for reversing impaired function in the diabetic heart, preventing or delaying heart failure in patients with diabetes.