Tailoring Targeted Therapy To DNA Repair-defective High-Grade Serous Ovarian Cancer
Funder
National Health and Medical Research Council
Funding Amount
$802,247.00
Summary
Ovarian cancer is a major cause of cancer death in women because current treatments are inadequate. Half of aggressive ovarian cancers have abnormalities in DNA repair and should be susceptible to new PARP inhibitor therapy, yet not all those respond. By developing a new model of studying human ovarian cancers in mice, we can discover markers to predict which ovarian cancers will respond best to these exciting new treatments.
A Study Of The Molecular Epidemiology And Virulence Determinants Of Enterovirus 71 Strains From The Asia-Pacific Region
Funder
National Health and Medical Research Council
Funding Amount
$286,325.00
Summary
In this study, we aim to understand the reasons for the emergence of epidemics of severe neurological disease due to enterovirus 71 (EV71) in young children of the Asia-Pacific region since 1997, and to develop strategies for disease prevention. EV71 is a human enterovirus closely related to the polioviruses. Most infections with EV71 are trivial, however, they may occasionally result in severe disease, including brainstem encephalitis with a high mortality and acute flaccid paralysis similar to ....In this study, we aim to understand the reasons for the emergence of epidemics of severe neurological disease due to enterovirus 71 (EV71) in young children of the Asia-Pacific region since 1997, and to develop strategies for disease prevention. EV71 is a human enterovirus closely related to the polioviruses. Most infections with EV71 are trivial, however, they may occasionally result in severe disease, including brainstem encephalitis with a high mortality and acute flaccid paralysis similar to poliomyelitis. There has been a large increase in EV71 epidemic activity throughout the Asia-Pacific region since 1997, including a large epidemic in Perth, Western Australia in 1999. These epidemics have resulted in many deaths and cases of severe neurological disability. In view of the severity of EV71 neurological disease and the lack of effective treatments, our research effort needs to focus on prevention through public health surveillance and vaccine development. The major aims of our study are two-fold: 1. To study the origin and evolution of EV71 in the Asia-Pacific region using molecular techniques and to use this information to implement surveillance in Australia and Southeast Asia. It is anticipated that improved surveillance will provide early warning of impending epidemics. 2. To understand the molecular basis of virulence of EV71, with emphasis on the ability of virus to cause severe disease of the central nervous system. This study will have two goals: a. To identify the human cellular receptor of EV71. The ultimate goal of this research will be the development of a small animal model of EV71 encephalitis by constructing a transgenic mouse expressing the human cellular receptor for EV71. b. To construct an infectious cDNA clone of EV71 and to develop genetically defined attenuated strains by mutagenesis of the infectious clone. Mutant strains of EV71 will be tested for replication and virulence in newborn mice and in human neuroblastoma cells.Read moreRead less
Evolutionary Genomics Approaches For Studying Acquisition Of Drug Resistance In Tumours
Funder
National Health and Medical Research Council
Funding Amount
$313,390.00
Summary
Chemotherapy often fails because some of the cells in tumour evolve resistance to the drugs the patient is given, causing relapse. We study how a tumour’s unstable genome and high rate of mutation drives its evolution by observing tumour cells in the laboratory as they evolve resistance to drugs and the genetic differences between resistant and sensitive cells. This work will help develop therapeutic strategies to prevent tumours from evolving resistance to chemotherapy.
Dissecting insect gut function to understand insecticide detoxification. Massive quantities of chemical insecticides are used daily to control the insect pests that threaten agriculture, human health and the welfare of domestic pets. Insects readily evolve resistance to these chemicals reducing the effectiveness of pest control, increasing the amount of chemical used and increasing costs to consumers. This project examines the way in which insects adapt to the extreme stress imposed on them by ....Dissecting insect gut function to understand insecticide detoxification. Massive quantities of chemical insecticides are used daily to control the insect pests that threaten agriculture, human health and the welfare of domestic pets. Insects readily evolve resistance to these chemicals reducing the effectiveness of pest control, increasing the amount of chemical used and increasing costs to consumers. This project examines the way in which insects adapt to the extreme stress imposed on them by chemical insecticides. A thorough understanding of this adaptation process is required before insecticide resistance can be effectively managed or prevented. Read moreRead less
Adaptive Evolution of BRCA1 in Ancestral Mammals. This project investigates adaptive evolution of BRCA1 in the early radiation of mammals. We will test the hypothesis that the evolution of mammary glands and X chromosome inactivation has resulted in modification of the BRCA1 protein sequence as it aquired new roles in these processes. We will also investigate the importance of these changes inducing compensatory changes in other parts of the protein.
Further Genetic and Molecular studies of an Important Prokaryotic Regulator Protein TyrR. Genomes encode many functions whose expression varies dramatically depending on particular cellular environments. Special proteins called Regulator Proteins act as sensors to detect subtle changes in the environment and, in response, to influence the expression of certain genes either dampening them down or stimulating their activity. We are working with the TyrR regulator protein of the simple bacterium E ....Further Genetic and Molecular studies of an Important Prokaryotic Regulator Protein TyrR. Genomes encode many functions whose expression varies dramatically depending on particular cellular environments. Special proteins called Regulator Proteins act as sensors to detect subtle changes in the environment and, in response, to influence the expression of certain genes either dampening them down or stimulating their activity. We are working with the TyrR regulator protein of the simple bacterium Escherichia coli to elucidate the molecular strategies used in these controls. Because this protein controls the expression of a number of genes with diverse functions, evolution has selected equally diverse mechanisms to achieve appropriate transcriptional responses. The detailed knowledge of the E.coli genome and of the various genes regulated by TyrR make it an excellent system for such fundamental studies.Read moreRead less
Genetic And Functional Analysis Of Brain Malformations
Funder
National Health and Medical Research Council
Funding Amount
$105,327.00
Summary
Disorders of early brain development are recognised as a significant cause of illness and disability in children. Unfortunately, the causes of these conditions are poorly understood, and treatment options are limited. It has become apparent that many of these conditions have an underlying genetic basis. This project will identify genes that regulate brain development and aid the development of improved treatment programs for brain and mind disorders.
Using comparative genomics to identify genes responsible for adaptation to environmental toxins. The US National Human Genome Research Institute has committed to sequencing the genomes of ten different Drosophila (fly) species. We will search these genomes, and two others that are already available, for genes that allow flies to cope with environmental toxins found in the plants upon which they feed and breed. These same genes have the potential to degrade many of the insecticides used to con ....Using comparative genomics to identify genes responsible for adaptation to environmental toxins. The US National Human Genome Research Institute has committed to sequencing the genomes of ten different Drosophila (fly) species. We will search these genomes, and two others that are already available, for genes that allow flies to cope with environmental toxins found in the plants upon which they feed and breed. These same genes have the potential to degrade many of the insecticides used to control insect pests. Hence, this research will contribute to ongoing efforts to minimize the threat to agriculture posed by the insecticide resistance that frequently evolves in pest species. Read moreRead less
Expanding Diagnostic Approaches For Lynch Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$1,269,355.00
Summary
Currently, there are ~1,000 families who have attended Family Cancer Clinics across Australia who have the hallmarks of having Lynch syndrome, a hereditary bowel cancer syndrome, but who have no gene defect identified, i.e. their cancer is unexplained. Clinicians are challenged by these “Lynch-like” patients as their family cancer risk is unknown. Our research has identified new gene defects in Lynch-like patients. Our aim is to optimise clinical testing approaches for Lynch-like patients.
A Functional Assay To Classify Genetic Variants In Lynch Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$368,195.00
Summary
At least one person in every 1000 is affected by Lynch syndrome, in which faulty DNA repair machinery causes high rates of cancer. People with Lynch syndrome can have their risk of cancer cut substantially with regular screening. However, we often struggle to understand whether people with 'non-standard' DNA sequences in particular genes actually have Lynch syndrome. This project develops a simple test that will tell clinicians whether a given sequence change relates to Lynch syndrome or not.