A Novel Molecular Target Capable Of Abrogating Neuroblastoma Development
Funder
National Health and Medical Research Council
Funding Amount
$802,499.00
Summary
Although modern chemotherapy has significantly improved survival rates for many childhood cancers, the outlook remains dismal for children with advanced staged neuroblastoma. These patients frequently have alterations in the cancer-causing gene called MYCN. Using pre-clinical models of MYCN-driven neuroblastoma and genome sequencing we have discovered a gene that can completely block the action of MYCN and prevent neuroblastoma growth. This work will characterize the function of this novel gene.
Stress-induced Genomic Instability As A Driver Of Adaptive Responses In Human Cancer Cells
Funder
National Health and Medical Research Council
Funding Amount
$690,426.00
Summary
Growing experimental evidence suggests human cancer cells use evolutionary conserved programs to regulate their mutation rates in response to pharmacological agents, accelerating adaptation and the emergence of resistance. The purpose of our study is to identify the common molecular pathways and genetic mechanisms driving the regulation of mutation rates. Targeting of these pathways using a new generation of “anti-evolution” drugs is an attractive possibility for novel therapeutic approaches.
Identifying Novel Antimalarial Targets Using ENU Mutagenesis In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$760,170.00
Summary
Malaria is estimated to cause 1.2 million deaths per year. The malarial parasite has developed resistance to most drugs and new drugs are needed. We aim to mimic the protective red blood cell diseases common in human populations in malarial endemic areas by identifying host targets that are important in parasite growth.
Dissecting The Molecular Basis For Emerging Alcohol Tolerance In VRE
Funder
National Health and Medical Research Council
Funding Amount
$836,620.00
Summary
Infections caused by vancomycin resistant Enterococcus faecium (VREfm) are a major and growing problem in health care facilities around Australia. We have observed that VREfm is becoming significantly more resistant to killing by alcohol, probably due the increasing use of alcohol-based hand wash products. This project will identify how VREfm is becoming alcohol tolerant, knowledge that will be used to develop alternative disinfection methods or other intervention strategies to stop its spread.
Somatic Gene Trapping In Schistosoma Mansoni _ The Key To Functional Analysis
Funder
National Health and Medical Research Council
Funding Amount
$623,270.00
Summary
Blood flukes are endemic in 76 countries and infect 300 million people worldwide. Control largely relies on the drug praziquantel. However, its wide scale use has led to concerns that drug resistance will develop. In this study we will use ñgene trap vectorsî to introduce insertional mutations into the schistosome genome. This will help to understand the function and importance of genes in biochemical pathways used by the parasite and to define effective targets for drug and vaccine development.
Hepatocellular Carcinoma: Understanding The Genotoxic Risks Of Liver-targeted Gene Therapy Using Recombinant AAV Vectors
Funder
National Health and Medical Research Council
Funding Amount
$891,639.00
Summary
Advances in gene transfer technology using an engineered virus known as AAV underpin success in the treatment of haemophila B, and offer the exciting prospect of treating many other liver diseases. While continued improvement of gene transfer efficiency is essential there is an equal need to focus on safety. We have discovered a genetic element in AAV that we believe is a key to unlocking accurate analysis of the safety of AAV-based gene transfer technology. Here we propose to turn the key.
Analysis And Manipulation Of The Genome-wide Integration Signatures Of Gamma-retroviral And Lentiviral Vectors In Human Haematopoietic Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$612,154.00
Summary
Gene therapy has been successful in treating several diseases involving the bone marrow, but has been associated with the development of leukaemia in a number of patients. The cause has been tracked to the gene transfer technology used and associated damage to the genetic blueprint of treated cells. In this study we plan to use high-throughput genetic analysis to better understand the nature of this damage and to develop strategies to improve the safety of the gene repair process.
The Structural Basis For Biased Agonism At The Glucagon-like Peptide-1 Receptor
Funder
National Health and Medical Research Council
Funding Amount
$872,536.00
Summary
The glucagon-like peptide-1 receptor plays an essential role in nutrient-regulated insulin release, and is a major target for therapeutic treatment of type 2 diabetes. The binding of different drugs to this receptor can promote distinct signalling profiles inside the cell that can lead to different physiological outcomes. Understanding the mechanistic basis for this will provide a framework to enable rational design of novel, better and safer therapeutics for the treatment of diabetes.
Many drugs modulate the function of proteins imbedded in cell membranes. Extensive research has been undertaken to better understand drug interactions with these proteins to improve drug therapies, but there has been relatively little progress in understanding the role of the cell membrane. This project will investigate how the cell membrane influences protein function and then use this information to develop novel drugs for the treatment of neurological disorders.
The Structural Basis For Glutamate Transporter Function
Funder
National Health and Medical Research Council
Funding Amount
$373,144.00
Summary
Glutamate transporters are vacuum cleaners in the brain that suck the neurotransmitter glutamate into cells. When the glutamate vacuum breaks down or becomes blocked, glutamate levels outside cells increase, leading to cell death in the brain. This process underlies the damage in many brain diseases including Alzheimer’s disease and stroke. The aim of this project is to understand the mechanism of the glutamate vacuum cleaner so we can develop therapeutics to fix it when it breaks down.