Regulation Of Subcellular Localisation Of Respiratory Syncytial Virus M Protein: Implications For Pathology
Funder
National Health and Medical Research Council
Funding Amount
$580,195.00
Summary
Respiratory syncytial virus (RSV) is the major cause of viral pneumonia in infants and the elderly, causing more deaths in winter than influenza. We have observed RSV M protein in the nucleus of infected host cells where it inhibits host cell transcription. We propose to investigate the regulation of nuclear localisation of M by phosphorylation and binding to cellular factors and its importance to RSV pathogenesis. The results will relate strongly to future drug and vaccine development.
A New Non-invasive Diagnostic Technique Based On Detection Of Exhaled Respiratory Pathogens.
Funder
National Health and Medical Research Council
Funding Amount
$179,300.00
Summary
We developed a special collection mask and showed that the breath of people with colds or flu contains a tiny amount of virus. Currently, diagnostic samples are collected by putting a tube into the airways - this is very uncomfortable. Our masks may provide a new and more comfortable way to diagnose lung infections. We want to build better masks and ways to detect viruses and bacteria to test out this method. This may create a new test that will improve diagnosis and treatment.
Evolution Of Airway Function And Inflammation In Early Cystic Fibrosis Lung Disease
Funder
National Health and Medical Research Council
Funding Amount
$494,447.00
Summary
Our goal is to evaluate if lung function can identify the onset of early lung disease in infants with cystic fibrosis (CF). We aim to evaluate: - Changes in lung function in infants with CF. - Associations between lung function and lung inflammation and infection. - Links between infant lung function and disease severity at 2 years of age. The long term aims are to determine how useful lung function will be in trials of novel treatments for the early treatment of CF.
Correction And Measurement Of The Basic Defects In Cystic Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$929,335.00
Summary
Airway disease caused by the genetic disease cystic fibrosis (CF) cannot currently be prevented or cured. Current treatments (other than lung transplant) can only slow the inevitable decline in lung health. Early death from lung failure occurs for many with CF. We have developed a gene transfer technique to introduce the corrective gene (CFTR) into CF-diseased airway cells. We have used airways in mice to test and develop this method, to determine if long-lasting genetic correction of the airway ....Airway disease caused by the genetic disease cystic fibrosis (CF) cannot currently be prevented or cured. Current treatments (other than lung transplant) can only slow the inevitable decline in lung health. Early death from lung failure occurs for many with CF. We have developed a gene transfer technique to introduce the corrective gene (CFTR) into CF-diseased airway cells. We have used airways in mice to test and develop this method, to determine if long-lasting genetic correction of the airway cells can be achieved. The gene is introduced into the airway as a single small dose of special delivery-particles (vector) that have been built using highly-modified components of the HIV-1 virus. If ultimately successful in humans with CF, the disease should be halted, or even cured. Our recent work indicates that we have been able to insert the gene into airway progenitor cells, confirming our hypothesis that long-lasting gene expression can be achieved this way. To know if the method would be safe and effective in humans, we must now test the technique in sheep (as a human-size lung) and in marmosets (as a human-like lung) before clinical trials could be considered. We will monitor animals for up to 3 years to be sure the effect of the gene is truly long-lasting, and we will document how the gene-transfer vector disappears from the body. We have also discovered a new way to examine the detail of the very thin fluid layer on the airway surface. This fluid is too shallow in CF airway (allowing bacteria to stick and start disease) and so a successful gene therapy should return the fluid to it's proper depth. This method uses X-ray light from a synchrotron, and we expect it will work without the need to sacrifice animals to measure the airway surface. If successful it also has potential to be used much like a normal X-ray in humans with CF, to test if a gene therapy has worked.Read moreRead less
Synchrotron X-ray Assessment Of Airway Surface Physiology For Cystic Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$778,228.00
Summary
We seek a cure or long-lasting therapy for the fatal airway disease in cystic fibrosis. Disease is caused by a shallow and dehydrated airway surface liquid (ASL), allowing bacteria to infect the lung. We can introduce a corrective gene into mouse airways where it can be effective for over 1 yr, but no fast, accurate and non-invasive measurement exists to test if treatments are successful. We will develop methods using synchrotron light to directly measure ASL depth changes in live mouse airways.
Pneumovirus Infection In Infancy Affects The Development Of Life-long Adaptive Immunity.
Funder
National Health and Medical Research Council
Funding Amount
$408,469.00
Summary
Respiratory syncytial virus is the most important cause of acute lower respiratory tract infection (RTI) in young children worldwide. Hospital admission rates in Western societies for RTIs are around 3% for children younger than 1 year. A vaccine to RSV is not yet available and repeat infections occur thoughout life, suggesting that the immune response does not develop correctly. In this project we are exploring the mechanisms that underpin disease development and promote incomplete immunity.
Long-lasting Correction Of The Basic Defect In Cystic Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$458,500.00
Summary
The airway disease caused by the genetic disease cystic fibrosis (CF) is not yet preventable. Current treatments can only limit the gradually-increasing lung disease and is costly. Our new gene therapy technique introduces a correcting gene into affected airway cells, and it has already worked in the first tests in mice bred with CF. Airways in mice are used to test whether the effect is reliable, effective, and lasts long enough to be useful. The gene is introduced into the airway using special ....The airway disease caused by the genetic disease cystic fibrosis (CF) is not yet preventable. Current treatments can only limit the gradually-increasing lung disease and is costly. Our new gene therapy technique introduces a correcting gene into affected airway cells, and it has already worked in the first tests in mice bred with CF. Airways in mice are used to test whether the effect is reliable, effective, and lasts long enough to be useful. The gene is introduced into the airway using special virus delivery-particles, after conditioning the airway to make it receptive to the particles. The method works in normal mice and in CF mice; it gives long lasting gene transfer from a single dose and seems to affect all airway cell types. The gene transfer may also be occurring in airway stem cells, i.e. the mother cells from which grow all the cells of the airway surface. Until now, no-one else has been able to produce prolonged gene transfer in this way, nor arrange gene transfer into stem cells in live airways. There are now a number of things that we must investigate before we could conduct safety and effectiveness trials in larger animals, or consider moving into clinical trials in humans. We need to understand exactly how our conditioning agent works and is it safe; measure how long the gene correction can last actually in our animals; decide if we can we re-dose animals (if needed) without losing effectiveness because of inflammation or immune responses that might occur; and decide how important the airway stem cells are in producing the length of the gene transfer. Because it has been difficult to measure gene correction in CF airways, we will also test new ways we have developed to measure how well the gene correction works in CF airways. The findings of this project will allow us to develop our method to where we can test it in larger animals, to provide a strong, long-lasting gene correction that will be safe for testing in human clinical trials.Read moreRead less
CHARACTERISATION OF NOVEL PICORNAVIRUS-LIKE VIRUSES IDENTIFIED FROM PATIENTS WITH ACUTE RESPIRATORY INFECTIONS.
Funder
National Health and Medical Research Council
Funding Amount
$366,998.00
Summary
The common cold and serious chest colds are usually due to viral infections, and mostly occur in children. Unfortunately we can only be certain of the virus causing this illness in as little as 15% of cases. We intend to address this lack of research by examining, in detail, a new virus we recently identified in a child with serious respiratory illness that required admission to hospital. Testing by our laboratory suggests that the new virus is related to picornaviruses (which cause some common ....The common cold and serious chest colds are usually due to viral infections, and mostly occur in children. Unfortunately we can only be certain of the virus causing this illness in as little as 15% of cases. We intend to address this lack of research by examining, in detail, a new virus we recently identified in a child with serious respiratory illness that required admission to hospital. Testing by our laboratory suggests that the new virus is related to picornaviruses (which cause some common colds) but seems to be present in children with far more serious illness. Our study plans to more completely identify the new picornavirus-like virus (PLV) using the tools of molecular biology and the expertise of a senior team of Australian scientists and clinicians who have recently made several virus discoveries in Australia, demonstrating that Australian virus research is capable of achieving highly competitive results that benefit our hospitals and especially their young patients. Our studies will develop extremely sensitive tests which rely on the detection of very small amounts of the viral genome. We can use these tests to determine what the whole virus looks like, when it might occur during the year and whether the PLV are found worldwide. Our studies will also produce viral proteins in the laboratory and use these to make new tests for stored blood samples. If a blood sample comes from a patient who has previously been infected by PLV, their blood will contain specific antibodies which we will then be able to detect. We also intend to determine whether some strains of PLV are more or less likely to cause serious illness than others. Improved understanding of these and other viruses minimises the chance of illness spreading within a hospital, helps scientists to decide against which viruses to design vaccines and drugs and aids medical doctors to better identify what once went undiagnosed.Read moreRead less
Inhibition Of IFN-?/? By Human Metapneumovirus And The Induction Of Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$605,251.00
Summary
The newly isolated human metapneumovirus (hMPV) causes significant respiratory illness in infants, young children and the elderly. The virus can persist long-term and may predispose individuals to chronic lung disease. This proposal aims to determine the mechanisms by which hMPV infection causes respiratory disease, with a view to improving treatments and preventing disease.