Kidney transplantation is the only cure for end-stage kidney disease. Although drugs are used to prevent rejection of the new kidney, there is significant inter-individual variability in patients' repsonse. Many factors are involved including age, other diseases and use of other drugs. Individual's genetic make up may also contribute to this variability. This study will show how variability in genes that control drug transport and action affect the risk of rejection and long-term kidney function ....Kidney transplantation is the only cure for end-stage kidney disease. Although drugs are used to prevent rejection of the new kidney, there is significant inter-individual variability in patients' repsonse. Many factors are involved including age, other diseases and use of other drugs. Individual's genetic make up may also contribute to this variability. This study will show how variability in genes that control drug transport and action affect the risk of rejection and long-term kidney function.Read moreRead less
Modulation Of Apoptosis By Cytomegalovirus: Analysis Of New Mechanisms To Interfere With Cytomegalovirus-induced Disease
Funder
National Health and Medical Research Council
Funding Amount
$697,084.00
Summary
Apoptosis, or programmed cell death is an essential process in developmental and homeostatic control of complex biological systems. In addition to these primary house keeping roles, apoptosis provides a powerful defence mechanism against invading pathogens, such as viruses, since it allows early elimination of infected cells from the host. A basic property of herpesviruses is their ability to establish persistent infection and remain in association with the host for its lifetime. This strongly u ....Apoptosis, or programmed cell death is an essential process in developmental and homeostatic control of complex biological systems. In addition to these primary house keeping roles, apoptosis provides a powerful defence mechanism against invading pathogens, such as viruses, since it allows early elimination of infected cells from the host. A basic property of herpesviruses is their ability to establish persistent infection and remain in association with the host for its lifetime. This strongly underlines their success at reaching an accommodation with the immune system's anti-apoptotic mechanisms. The central hypothesis of this project is that herpesviruses, such as murine and human cytomegalovirus, encode proteins that interfere with cell death pathways thereby circumventing host defence so that viral replication and dissemination can proceed. Thus, the aims are to identify and characterise cytomegalovirus proteins that modulate apoptosis. These studies will improve our understanding of the control of apoptosis during viral infection, especially as caused by cytomegaloviruses. Human cytomegalovirus (HCMV) is a pathogen able to cause significant morbidity and mortality in individuals with immature or compromised immune systems, such as newborns, AIDS patients, transplant recipients and people treated with chemotherapeutic drugs. Hence, the proposed studies will allow the elucidation of molecular mechanisms that may be relevant to the pathogenesis of HCMV in man and will provide insights into the rational design of suitable antiviral drugs and vaccines. Understanding viral mechanisms of host immune evasion continues to improve our understanding of complex cellular pathways. Therefore, given that abnormal regulation of apoptosis is implicated in the development of degenerative conditions, cancer and autoimmune disease, the proposed studies will provide valuable insight towards the development of new therapies for these pathological conditions.Read moreRead less
Multiple Cytomegalovirus Infections: Biological And Evolutionary Significance.
Funder
National Health and Medical Research Council
Funding Amount
$555,776.00
Summary
This project involves the study of cytomegalovirus (CMV) a common viral infection of humans which normally cause little disease. However in individuals whose immune system is suppressed (such as AIDS patients or transplant recipients), or in infection of pregnant women, CMV can cause serious or life-threatening disease in the patient or foetus. An interesting feature of CMV diseases in such patients is that enhanced viral growth and more severe disease is frequently associated with the presence ....This project involves the study of cytomegalovirus (CMV) a common viral infection of humans which normally cause little disease. However in individuals whose immune system is suppressed (such as AIDS patients or transplant recipients), or in infection of pregnant women, CMV can cause serious or life-threatening disease in the patient or foetus. An interesting feature of CMV diseases in such patients is that enhanced viral growth and more severe disease is frequently associated with the presence of multiple strains of CMV in the patient. We suggest that mixed CMV infections provide a survival advantage to the virus, with different strains within the mixed infection assisting the growth of other strains. This would result in increased virus growth overall, and enhanced disease. To study the mechanisms by which multiple infections with different CMV strains may affect both the virus and the host, experiments will be performed using an animal model of CMV, murine cytomegalovirus (MCMV). We will examine the effect of the presence of multiple strains of virus on virus growth and distribution within the infected host. We will also determine if functional MCMV strains are capable of assisting non-functional strains to survive within the host. These studies are relevant to the design of a CMV vaccine, and will be valuable in revealing the ways in which viruses can co-operate within an infection.Read moreRead less
Role Of Cytomegalovirus Class I Homologue In Interference With Host NK Cell Responses - A Potential Antiviral Target
Funder
National Health and Medical Research Council
Funding Amount
$428,020.00
Summary
A common property of herpesviruses such as cytomegalovirus is their ability to establish lifelong infection in their hosts. In humans, cytomegalovirus infection can lead to tissue damage in normal individuals and may cause severe disease and even be fatal in individuals with immature or compromised immune systems, such as newborns, AIDS patients, transplant recipients and people treated with chemotherapeutic drugs. The ability of these viruses to establish persistent infection and remain in asso ....A common property of herpesviruses such as cytomegalovirus is their ability to establish lifelong infection in their hosts. In humans, cytomegalovirus infection can lead to tissue damage in normal individuals and may cause severe disease and even be fatal in individuals with immature or compromised immune systems, such as newborns, AIDS patients, transplant recipients and people treated with chemotherapeutic drugs. The ability of these viruses to establish persistent infection and remain in association with the host for its lifetime is a consequence of their capacity to subvert normal host immune responses. This is achieved by destroying or mimicking the functions of molecules and-or pathways critical to normal host defence mechanisms. The viral gene product under investigation is similar to a cellular protein critical for the ability of immune cells to kill foreign and-or infectious agents. We will investigate the mechanisms by which this viral gene product interferes with the host's first line of defence against viral pathogens. The proposed studies will improve our understanding of the strategies used by viruses to escape normal host immune responses and hence provide insights into the rational design of antiviral drugs and vaccines. Since the viral protein under investigation is similar to a cellular protein essential for the ability of immune cells to kill foreign or infectious agents, an improved understanding of the mechanisms of action of this protein will continue to improve our understanding of cellular events which play a crucial role in immune responses involved not only in control of infection, but also in tumour growth and transplant survival. Thus, the proposed studies will provide valuable insight towards the development of new therapies for pathological conditions associated with the above.Read moreRead less
Genetic Dissection Of The Biogenesis And Function Of Type IV Fimbriae Of Pseudomonas Aeruginosa
Funder
National Health and Medical Research Council
Funding Amount
$407,545.00
Summary
Pseudomonas aeruginosa is a common bacterium which causes serious life-threatening infections of individuals with cystic fibrosis, AIDS or who have suffered severe burns or are undergoing cancer chemotherapy. This pathogen, and a number of other important infectious bacteria use surface filaments, called fimbriae, like grappling hooks to attach to the cells of the body and to move across host tissues. These fimbriae are produced in response to environmental conditions, and are assembled by a pro ....Pseudomonas aeruginosa is a common bacterium which causes serious life-threatening infections of individuals with cystic fibrosis, AIDS or who have suffered severe burns or are undergoing cancer chemotherapy. This pathogen, and a number of other important infectious bacteria use surface filaments, called fimbriae, like grappling hooks to attach to the cells of the body and to move across host tissues. These fimbriae are produced in response to environmental conditions, and are assembled by a process that is also used in the export of toxins and other pathogenic molecules. This project will characterise genes which specify and control this system, as a means to design better treatments against such bacteria, many of which are resistant to antibiotic treatment.Read moreRead less
Analysis Of A Chemosensory Complex That Controls Twitching Motility And Virulence In Pseudomonas Aeruginosa
Funder
National Health and Medical Research Council
Funding Amount
$346,250.00
Summary
Pseudomonas aeruginosa is a common bacterium which causes serious life-threatening infections of individuals with cystic fibrosis, AIDS or who have suffered severe burns or are undergoing cancer chemotherapy. Infection by this pathogen requires the controlled expression of a large number of virulence factors including extracellular enzyme, toxins and structures for the attachment and colonisation of host tissues. We have identified a complex multicomponent regulatory system which coordinates the ....Pseudomonas aeruginosa is a common bacterium which causes serious life-threatening infections of individuals with cystic fibrosis, AIDS or who have suffered severe burns or are undergoing cancer chemotherapy. Infection by this pathogen requires the controlled expression of a large number of virulence factors including extracellular enzyme, toxins and structures for the attachment and colonisation of host tissues. We have identified a complex multicomponent regulatory system which coordinates the expression of many of the virulence determinants of this pathogen. This project aims to dissect the intermolecular interactions and signalling events which input into, occur within, and output from this regulatory system. This knowledge will provide a platform for developing rational strategies for the production of new antimicrobials for fighting infections by this and related pathogens.Read moreRead less
Protecting Hyposplenic Children And Adults: Identifying Optimal Immunisation Regimens
Funder
National Health and Medical Research Council
Funding Amount
$472,044.00
Summary
Children and adults without normal spleen function are at massively increased risk of overwhelming infection with the pneumococcus bacteria, with 200 times the risk of death from sepsis compared with the normal community. Poor spleen function can be due to an absent spleen (eg after surgery following a car accident) or an underlying medical condition (eg thalassaemia or cancer therapy). Thousands of Australians are affected by this condition and need extra protection from daily antibiotics and a ....Children and adults without normal spleen function are at massively increased risk of overwhelming infection with the pneumococcus bacteria, with 200 times the risk of death from sepsis compared with the normal community. Poor spleen function can be due to an absent spleen (eg after surgery following a car accident) or an underlying medical condition (eg thalassaemia or cancer therapy). Thousands of Australians are affected by this condition and need extra protection from daily antibiotics and additional immunsiations against pneumococcus. A new vaccine against pneumococcus was introduced for Australian infants routinely in 2005 and has prevented many from developing pneumococcal meningitis, sepsis and pneumonia. We wish to see whether this new vaccine, when used with the older existing pneumococcal vaccine, will better protect older children and adults with poor spleen function from the devastating effects of pneumococcus. We will compare different ways of using these vaccines to try to identify the most protective vaccination plan for this vulnerable group of Australians.Read moreRead less
Understanding Burn Injuries In Aboriginal And Torres Strait Islander Children: Treatment, Access To Services And Outcomes.
Funder
National Health and Medical Research Council
Funding Amount
$911,798.00
Summary
This is the first large scale study to systematically examine the burden of burn injury in Aboriginal and Torres Strait Islander children, including care and cost of treatment, and relationship between access to treatment and functional outcomes. With a team comprising epidemiologists, burns clinicans and Aboriginal health researchers, this study will generate important new research evidence to improve care in this over-represented and vulnerable population.