Therapeutic Regulation Of Matrix Metabolism To Stabilise The Biomechanical Properties Of The Sclera In High Myopia
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Myopia (short-sightedness) is due to the eye being too long. It is a common refractive disorder, affecting some 25-30% of people in developed countries, and results in blurred distance vision. Most myopia is easily correctable with spectacles or contact lenses. However a small, but significant, group of individuals have excessively long eyes and extreme amounts of myopia. These enlarged eyes impose abnormal stresses on the structures inside, particularly affecting the retina which is the light s ....Myopia (short-sightedness) is due to the eye being too long. It is a common refractive disorder, affecting some 25-30% of people in developed countries, and results in blurred distance vision. Most myopia is easily correctable with spectacles or contact lenses. However a small, but significant, group of individuals have excessively long eyes and extreme amounts of myopia. These enlarged eyes impose abnormal stresses on the structures inside, particularly affecting the retina which is the light sensitive part of the eye. Any damage that occurs to the retina in these eyes is, at present, untreatable and irreversible and can result in blindness. In fact, myopia is the 2nd leading cause of blindness amongst adults of working age. In order for the eye to grow so large its white, outer coat (the sclera) must expand without allowing any leaks of the delicate structures and fluids inside. Although the sclera gets very thin as it expands, it has been shown that this process of expansion is not just due to stretching. Before any stretching can occur the biochemical structure of the sclera must change. A complex process, involving the synthesis of structural components and the activity of enzymes that breakdown these structural components, is at work in the sclera of eyes that are rapidly enlarging. The aim of this project is to intervene in the biochemical processes that have already been shown to be involved in excessive eye enlargement. We will use both therapeutic agents and innovative gene therapy techniques to reverse the biochemical changes that occur in the sclera of rapidly enlarging eyes. We predict that these therapies will result in a sclera that is more resistant to being stretched and an eye that has less pathology. The results from this study will provide us with potential therapeutic strategies for the treatment of eyes that are enlarging excessively, thereby giving us the opportunity of preventing blindness in a number of highly myopic individuals.Read moreRead less
Functional Analysis Of The Ym2 Chitinase-like Lectin In Allergic Airways Disease
Funder
National Health and Medical Research Council
Funding Amount
$283,767.00
Summary
The prevalence of asthma is widespread and nationally affects over two million Australians. Consequently, one of the Country s National Health Priorities is to improve our understanding of this condition. Analyses of the asthmatic lung reveal an airway wall that is thickened, an airway lumen that is obstructed and abnormal spasmogenicity of the airway smooth muscle: processes that collectively contribute to both acute and chronic respiratory dysfunction. Asthmatics develop an immune response tha ....The prevalence of asthma is widespread and nationally affects over two million Australians. Consequently, one of the Country s National Health Priorities is to improve our understanding of this condition. Analyses of the asthmatic lung reveal an airway wall that is thickened, an airway lumen that is obstructed and abnormal spasmogenicity of the airway smooth muscle: processes that collectively contribute to both acute and chronic respiratory dysfunction. Asthmatics develop an immune response that is biased toward production of allergy-related T helper 2 cytokines of which interleukin (IL)-13 is a potent mediator of disease. However, the molecular processes linking IL-13 with abnormal airway wall changes are unclear. To identify previously uncharacterised IL-13-related molecules, we used a protein profiling approach that identified a novel lectin (carbohydrate-binding protein) termed Ym2, which is secreted abundantly into the airway fluid of mice in which allergic airways disease has been induced. Preliminary studies suggest that Ym2 is an intermediary of IL-13 that is involved in respiratory dysfunction. This project aims to work out how Ym2 interacts with the molecules and cells of the respiratory tract to regulate allergic disease. Specific inhibitors of Ym2 will be developed to examine what happens to allergic responses when Ym2 can t function; transgenic mice will be developed to determine if we see features of allergy when Ym2 is over-expressed in the normal lung, and human samples will be screened to identify the human counterpart of Ym2 and whether this counterpart is secreted into the lung fluid of asthmatics. Defining the mechanism by which Ym2 regulates the pathogenesis of allergic disease will not only contribute to our basic understanding of the processes underlying asthma pathology, but also generate new information for better design of therapeutics directed against specific mediators of this debilitating and widespread disease.Read moreRead less
Mast Cells - Bystanders Or Instigators Of Airway Remodelling In Asthma?
Funder
National Health and Medical Research Council
Funding Amount
$623,764.00
Summary
Current asthma treatments have little effect on changes to the breathing tubes in our lungs. The tubes are thickened and stiffer, with more muscle, blood vessels, matrix and mucus. We propose that a particular inflammatory cell, called a mast cell, causes these changes to the breathing tubes and we will find out how it does that. Thus this project will establish why and how the changes to the breathing tubes happen in asthma and reveal how best to target and reverse-prevent them in the future.
Peroxisome Proliferator Activated Receptor Gamma Is A Novel Therapeutic Target For Inflammation And Remodelling In Asthma
Funder
National Health and Medical Research Council
Funding Amount
$307,436.00
Summary
Asthma affects over 2 million Australians with 300 deaths each year. Current drugs are not always effective. A new approach is to reduce the thickening and stiffening of the airway muscle found in asthma. Rosiglitazone, an antidiabetic drug in current use, inhibits growth of airway muscle in the test tube and chest tightening in a mouse model of asthma. Cells from asthmatics will be used to confirm these positive findings, and to support rapid clinical evaluation of this drug to benefit patients ....Asthma affects over 2 million Australians with 300 deaths each year. Current drugs are not always effective. A new approach is to reduce the thickening and stiffening of the airway muscle found in asthma. Rosiglitazone, an antidiabetic drug in current use, inhibits growth of airway muscle in the test tube and chest tightening in a mouse model of asthma. Cells from asthmatics will be used to confirm these positive findings, and to support rapid clinical evaluation of this drug to benefit patients.Read moreRead less
Effects And Mechanisms Of Direct Cardiac Compression In Interruption Of Myocardial Remodelling In Chronic Heart Failure.
Funder
National Health and Medical Research Council
Funding Amount
$392,250.00
Summary
Heart failure (HF) is a disease where the heart pumping function is insufficient to provide adequate blood supply to the rest of the body. It is a highly debilitating disease affecting nearly 10 million people worldwide and has a <50% one-year survival in severe cases. Despite significant advances in pharmacotherapy, heart transplant is the only alternative for severe HF but is restricted by lack of donor organs to only ~ 5% of those requiring it. Research has shown that progression of HF is ....Heart failure (HF) is a disease where the heart pumping function is insufficient to provide adequate blood supply to the rest of the body. It is a highly debilitating disease affecting nearly 10 million people worldwide and has a <50% one-year survival in severe cases. Despite significant advances in pharmacotherapy, heart transplant is the only alternative for severe HF but is restricted by lack of donor organs to only ~ 5% of those requiring it. Research has shown that progression of HF is related to many subsequent changes after an initial insult. In addition to pumping failure, HF is associated with deranged compensatory responses such as neurohumoral over-activation, heart chamber enlargement, loss of functional cells, increase of inflammatory mediators and changes in cardiac skeleton (extracellular matrix). The changes in the heart are collectively known as remodelling. Mechanical heart assist is now considered a potential destination therapy for severe HF, superior to pharmacotherapy alone. Improvement of cardiac pumping function and even successful weaning from devices has been reported, along with observations of reverse remodelling. The success of this approach has been limited however, particularly with HF due to coronary disease, the most prevalent form. We developed a novel HeartPatch mechanical assist device to compress the heart from its outer surface. It gives support to both main chambers and avoids blood contact, a feature of currently available devices associated with complications such as blood clotting and infection. Our device has proved effective in animals with acute HF and even with cardiac arrest. We propose to study the effects of our device on the process of remodelling in HF with coronary disease in a controlled manner. The project will enhance understanding of the mechanisms involved in reverse remodelling and further the development of a device which may potentially benefit many severe HF patients.Read moreRead less
Scarring And Angiogenesis In The Airway Wall In Smoking And COPD: Links Between Inflammation And Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$361,614.00
Summary
Smoking damages airways to produce scarring and new blood vessel growth resulting in airway narrowing, so-called COPD. Details of these processes are poorly understood. We will analyse airway biopsies taken from smokers, to dissect out the linkages between airway damage, airway inflammation, structural remodelling, and clinical changes. We will investigate the effects on these processes of: 1) inhaled corticosteroid; and 2) smoking cessation over 3 and 12 months.
The Cardiomyocyte Mineralocorticoid Receptor Plays A Critical Role In Cardiac Disease.
Funder
National Health and Medical Research Council
Funding Amount
$613,477.00
Summary
Drugs that block the mineralocorticoid receptor (MR), which responds to adrenal hormones, protect against heart disease and hypertension. We have shown that this effect is in part due to MR blockade in heart muscle cells. This novel finding is being explored further to understand the precise role of the MR in heart muscle cells in normal physiology and in disease. An understanding of the role of the MR in different tissues will enable development of tissue specific treatments for heart disease.
The Relationship Between Vascular Remodelling And Mast Cells In Chronic Asthma
Funder
National Health and Medical Research Council
Funding Amount
$353,253.00
Summary
It is known that the airwalls of asthmatics have increased numbers of small blood vessels which can contribute to poor lung function in asthma. The proposed research uses a novel sheep model for chronic asthma to investigate the progressive changes to the blood vessels in the airway walls of asthmatic lungs. The information gained from our sheep model will assist the understanding of blood vessel growth and thus ulitmately help in devising new strategies to treat the effects of asthma.