Pharmacological Strategy For Blocking Lung Cell Damage By Toxic Smoke Constituents.
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
People retrieved from burning buildings or other hazardous situations involving fires are often at risk of death due to the effects of inhaled smoke. This reflects the presence of some very toxic substances in smoke that are products of the combustion of wood, vegetation and synthetic building materials. The most toxic substance present within smoke is acrolein, a very reactive chemical that attacks cells in the lining of the lung. This can result in a life-threatening condition known as oedema, ....People retrieved from burning buildings or other hazardous situations involving fires are often at risk of death due to the effects of inhaled smoke. This reflects the presence of some very toxic substances in smoke that are products of the combustion of wood, vegetation and synthetic building materials. The most toxic substance present within smoke is acrolein, a very reactive chemical that attacks cells in the lining of the lung. This can result in a life-threatening condition known as oedema, where the lung is flooded with fluids and is unable to perform its respiratory function. At present, the clinical approaches used to treat smoke inhalation victims are mostly directed against offsetting the symptoms of lung injury and do not take into account the role of lung cell injury by toxic substances in smoke such as acrolein. This project will provide a better understanding of the chemical events underlying the injury caused by smoke to lung cells, and also into possible drug strategies for treating victims of smoke inhalation. The work will explore the ability of a range of compounds that are chemically related to a blood pressure-lowering medicine (hydralazine) to protect lung cells against such smoke-induced damage. The work will employ a range of modern research techniques to understand the events occurring in lung cells exposed to smoke. Once this is understood, these approaches will be used to test the various drug compounds for their abilities to prevent the death of cells exposed to smoke or its toxic constutuent acrolein. This work will yield new information on a series of compounds concerning their ability to block the toxicity of smoke to lung cells. The goal is to identify one or two molecules that can be carried forward to testing in smoke-exposed animals.Read moreRead less
A Novel Cytoskeletal Structure In Muscle Is Associated With Muscular Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$371,250.00
Summary
A NEW PROTEIN NETWORK IN MUSCLE IS ASSOCIATED WITH MUSCLE DISEASE An intricate protein network connects the contracting mechanism of a muscle to the surrounding cell membrane. Disruption of this connection is one of the known causes of muscular dystrophy. For many patients however the cause of the disease is unknown. We have identified a new region within this protein network that is also associated with muscle disease in mice. A number of proteins that are involved in transmitting chemical mess ....A NEW PROTEIN NETWORK IN MUSCLE IS ASSOCIATED WITH MUSCLE DISEASE An intricate protein network connects the contracting mechanism of a muscle to the surrounding cell membrane. Disruption of this connection is one of the known causes of muscular dystrophy. For many patients however the cause of the disease is unknown. We have identified a new region within this protein network that is also associated with muscle disease in mice. A number of proteins that are involved in transmitting chemical messages from one part of the muscle cell to another are found at this same location. It is possible that disruption of these messages may lead to muscle disease. This project aims to establish the nature of the relationship between the proteins found in this newly identified region of the protein network and muscle diseases such as muscular dystrophy, in both animal models and in humans. We expect that this project may identify new markers for identifying the cause of muscle diseases in some patients and lead to better hopes for an eventual cure.Read moreRead less
ISG60, A Novel Interferon-induced Protein: Cell Growth Inhibitory Actions
Funder
National Health and Medical Research Council
Funding Amount
$197,030.00
Summary
The interferons are signaling molecules produced by cells as part of an early warning sytsem to alert nearby tissue cells and immune cells to defend themselves against an impending viral attack or aberrant growth of cells. We have discovered ISG60, a new member of a group of proteins called the ISG54 family. The production of this family of proteins is turned on in all cells responding to the interferons. Exactly what the members of the protein family do within cells remains to be established. H ....The interferons are signaling molecules produced by cells as part of an early warning sytsem to alert nearby tissue cells and immune cells to defend themselves against an impending viral attack or aberrant growth of cells. We have discovered ISG60, a new member of a group of proteins called the ISG54 family. The production of this family of proteins is turned on in all cells responding to the interferons. Exactly what the members of the protein family do within cells remains to be established. However, by preparing cells which produce the ISG60 protein, we have found that it severely affects their growth, slowing the growth rate down and making the cells divide abnormally to become large, containing many nuclei and others dying. We propose that ISG60 binds to the structures involved in cell division and we have preliminary evidence that ISG60 interacts with an important protein involved in cell regulation, the retinoblastoma protein (pRb). The aim of this project is to more fully understand the role of ISG60 in cells. In particular, we aim to determine if ISG60 interacts with other important proteins inside cells. We shall explore the relationship of ISG60 function inside cells in greater detail as it should provide new insight into ways in which cell growth is regulated. This study will also provide insight into how the slowing of cell growth makes the cells less suitable for viral infection and reproduction, as well as providing new approaches for preventing the growth of cancer cells.Read moreRead less
Function Of The Flightless Protein In Wound Repair And Scar Formation In Skin
Funder
National Health and Medical Research Council
Funding Amount
$472,750.00
Summary
Scarring is the inevitable outcome of wound repair and can cover a spectrum of conditions, from normal fine lines to unsightly, restrictive and deforming scars. Each year in the world over 100 million patients acquire scars, primarily from surgical procedures. Many of these scars cause considerable problems. Over 4 million burn scars occur every year, 70% of them in children. Poor wound healing is a major clinical problem and can result in loss of movement and deformity. These are especially imp ....Scarring is the inevitable outcome of wound repair and can cover a spectrum of conditions, from normal fine lines to unsightly, restrictive and deforming scars. Each year in the world over 100 million patients acquire scars, primarily from surgical procedures. Many of these scars cause considerable problems. Over 4 million burn scars occur every year, 70% of them in children. Poor wound healing is a major clinical problem and can result in loss of movement and deformity. These are especially important considerations for children, where their growth places extra demands on healing wounds and grafts, necessitating regular surgical adjustment. Scarring is an area of largely unmet medical need and development of new treatment strategies would have significant impact on public health. Changes in cell adhesion, shape and movement are important processes in wound repair. A framework of filaments, much like guy-ropes that support a tent, help coordinate these events. Remodelling of these filaments, shortening or extending them and making new connections, allows cells to change shape and respond to stimuli. This is a crucial event in repairing wounds and the proteins that perform this are fundamentally important to wound repair. We have discovered a protein in skin, known as Flightless, that is involved in this filament remodelling process. The goal of this project is to determine what Flightless does in wound repair. By changing the amount of this protein and comparing its effect in non-scarring and scarring animal wound healing models we can gain insight into its role in wound healing and scar formation in humans. The development of new animal models in this research and the discovery of the role of Flightless in wound repair will provide exciting new opportunities to improve wound repair and reduce scarring, with significant impact on public health.Read moreRead less
Unified Model For Group A Streptococcal Invasive Disease Initiation.
Funder
National Health and Medical Research Council
Funding Amount
$605,221.00
Summary
Streptococcus pyogenes (group A streptococcus; GAS) is a bacterium that causes human skin and throat infections as well as highly invasive diseases including necrotising fasciitis and streptococcal toxic shock-like syndrome. We have recently discovered the trigger mechanism for GAS invasive disease. We hypothesise that the initial host response at the site of infection selects for a GAS invasive phenotype. We propose to examine the chain of events which result in tissue invasion in order to unde ....Streptococcus pyogenes (group A streptococcus; GAS) is a bacterium that causes human skin and throat infections as well as highly invasive diseases including necrotising fasciitis and streptococcal toxic shock-like syndrome. We have recently discovered the trigger mechanism for GAS invasive disease. We hypothesise that the initial host response at the site of infection selects for a GAS invasive phenotype. We propose to examine the chain of events which result in tissue invasion in order to understand these disease processes and allow the development of future therapeutic interventions.Read moreRead less
Role Of Bacteriophage-encoded Streptodornase In Invasive Disease Caused By Diverse Group A Streptococcal M Serotypes.
Funder
National Health and Medical Research Council
Funding Amount
$832,544.00
Summary
Streptococcus pyogenes (group A streptococcus, GAS) is estimated to cause ~700 million cases of self-limited throat or skin infection each year worldwide. Invasive GAS disease occurs in approximately 1-1000 cases, with associated mortality of 25%. We have recently discovered that a viral infection can reprogram GAS for invasive disease propensity. We will investigate whether this phenomenon is widespread, in order to understand this process and develop future therapeutics.
Immunotoxic Effects Of Engineered Nanomaterials Used In The Australian Workplace
Funder
National Health and Medical Research Council
Funding Amount
$586,816.00
Summary
Certain engineered nanomaterials are more toxic than their bulk material forms. We urgently need the ability to re-engineer these nanomaterials to reduce their toxicity and potential health risks, but lack the necessary knowledge. This project directly addresses the NHMRC Strategic Initiative on Nanotechnology and Health, by providing essential information for designing safer nanomaterials from systemically studying the immune effects of metal oxide nanoparticles used in Australian industry.
Understanding And Preventing Secondary Degeneration Following CNS Injury
Funder
National Health and Medical Research Council
Funding Amount
$409,147.00
Summary
After neurotrauma, tissue escaping initial injury undergoes secondary degeneration; tissue loss spreads, function worsens. In the complex brain and spinal cord it is difficult to distinguish vulnerable tissue. Using the visual system as a model I will precisely identify cells and processes of secondary degeneration, determine if vulnerable tissue can be rescued by drugs stopping toxic calcium influx and if rescued circuits work properly. The work has implications for neurotrauma and glaucoma.
ALCOHOL AND IMPAIRED LIVER REGENERATION: EFFECTS ON MITOGENIC SIGNALING PATHWAYS
Funder
National Health and Medical Research Council
Funding Amount
$365,295.00
Summary
Patients who regularly consume alcohol are slow to recover from liver injury because alcohol poisons the liver's capacity to regenerate itself (grow back). Hence patients with alcohol-induced liver disease have a high mortality and prolonged hospital stays. The applicants have been supported by NHMRC to study how alcohol impairs liver regeneration. They found that the effect is at the level of cell surface receptors for the growth factors that control liver regeneration. Alcohol alters the funct ....Patients who regularly consume alcohol are slow to recover from liver injury because alcohol poisons the liver's capacity to regenerate itself (grow back). Hence patients with alcohol-induced liver disease have a high mortality and prolonged hospital stays. The applicants have been supported by NHMRC to study how alcohol impairs liver regeneration. They found that the effect is at the level of cell surface receptors for the growth factors that control liver regeneration. Alcohol alters the function of these receptors. One major discovery has been that it damages the capacity to generate a rise in calcium within the cell, something that is fundamentally required for any cell to divide and reproduce itself. Thus when a rise in calcium was produced artificially (with chemicals to unlock the internal calcium stores), liver cells from alcohol-fed rats once more responded normally under the influence of growth factors and replicated themselves. The present work isdesigned to find out where this effect of calcium is exerted. The investigators believe that it is related to how other types of signals work, the so-called protein kinase pathways. These are cascades of one protein turning on (activating) the next down the line to ultimately switch on the genes that control cell growth. They will manipulate liver cells from alcohol-fed rats in culture to establish which of these pathways is most affected, and which is the most critical for the control of cell division genes. These studies will greatly advance our understanding about how alcohol impairs liver regeneration. They will give new insight into the control of liver cell growth and division that is such a crucial response of the liver to injury, vital for survival of the liver. This kind of knowledge will open the door for new treatments to be designed that can control liver growth - turn it back on when it has been poisoned, or turn it off when it is inappropriately vigorous and predisposing to liver cancer.Read moreRead less