Glycosyltransferase Effectors From Bacterial Enteric Pathogens
Funder
National Health and Medical Research Council
Funding Amount
$772,600.00
Summary
Many disease-causing microbes subvert host cell defences to establish infection in part by transporting virulence proteins, termed “effector” proteins, into host cells via specialized protein secretion systems. We have discovered a new family of bacterial effectors that modify host proteins with a sugar and thereby inactivate them. Here we will characterise the function of these effector proteins during infection with E. coli and Salmonella.
Glycosyltransferase Effectors Of Enteropathogenic E. Coli And Salmonella
Funder
National Health and Medical Research Council
Funding Amount
$320,891.00
Summary
This project aims to characterise the mechanisms of disease caused by bacterial pathogens including Salmonella and enteropathogenic E. coli. These pathogens cause a significant amount of diarrhoeal disease and mortality worldwide particularly in infants and in countries where water sanitation is poor. I aim to investigate the specific mechanisms the bacteria employ to manipulate and avoid our immune response during infection in order to better understand and combat diarrhoeal disease.
Modulating Sphingolipid Signalling To Enhance Wound Healing
Funder
National Health and Medical Research Council
Funding Amount
$698,447.00
Summary
Impaired wound healing is a major problem for diabetics, who often suffer with chronic unresolved wounds with serious effects on their quality of life and mortality. We have recently discovered a new pathway involving sphingolipids that shows great promise to improve wound healing in diabetics. In this project we will examine the targeting of this pathway, using existing and newly developed agents, to improve wound healing in advanced pre-clinical models of diabetes.
Structural And Biochemical Investigation Of The Bloom�s Complex, Defective In Bloom�s Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$184,661.00
Summary
Bloom�s Syndrome is a rare inherited disorder that results in greater than 90% risk of developing cancer by the age of 25. The gene that causes Bloom�s Syndrome, called BLM, protects cells from cancer-causing mutations hence affected individuals develop the same types of cancers as the general population, only much faster. We will investigate the properties of the BLM gene product and understand how it protects us from cancer, and may influence some forms of cancer treatment.
Biochemical Reconstitution Of The Ubiquitin Ligase Pathway Defective In Fanconi Anaemia
Funder
National Health and Medical Research Council
Funding Amount
$562,742.00
Summary
Fanconi Anemia (FA) is characterised by loss of vital blood cells but also 700x risk of developing leukaemia and other cancers. FA is caused by an inherited defect in one of 15 different genes that provide a signal and repair mechanism protecting cells from cancer causing mutations. By reconstructing this signaling mechanism in the test tube we will determine how it contributes to cancer protection, and highlight potential strategies for treatment of FA and leukaemia in the general population.
I am a structural biologist with a background in pharmacy. My research focuses on dissecting the molecular mechanisms of disease-causing proteins to underpin the development of new and improved therapeutics
Probing UDP-glucuronosyltransferase Protein-protein Interactions: The Power Of Two.
Funder
National Health and Medical Research Council
Funding Amount
$482,710.00
Summary
Drugs and other chemicals (eg. dietary constituents, environmental pollutants, and chemicals that occur naturally in the body - such as steroid hormones) are broken down by specialised proteins called enzymes. This process is referred to as biotransformation, or 'metabolism'. Drug and chemical metabolism serves as a detoxification mechanism (since the products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. UDP-Glucuronosyltransfera ....Drugs and other chemicals (eg. dietary constituents, environmental pollutants, and chemicals that occur naturally in the body - such as steroid hormones) are broken down by specialised proteins called enzymes. This process is referred to as biotransformation, or 'metabolism'. Drug and chemical metabolism serves as a detoxification mechanism (since the products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. UDP-Glucuronosyltransferase (UGT) is one of the most important enzymes involved in drug and chemical metabolism. Consistent with its ability to metabolise such a large number of compounds, UGT is known to exist as a 'superfamily' of structurally related proteins. Despite the importance of UGT, little is known about the structural characteristics of these enzymes that are responsible for recognising and binding different classes of chemicals. Accumulating evidence from this and other laboratories indicates that the individual UGT proteins may combine with themselves (to form a homodimer) and with other UGT proteins (to form heterodimers). This project largely seeks to define the scope of UGT homo- and hetero- dimerisation, identify the structural elements of the proteins responsible for association and characterise the functional significance of dimerisation. The project will further explore associations between UGTs and other proteins, namely albumin. Characterisation of UGT dimerisation and associations with other proteins is fundamental to our understanding of how this enzyme functions and selects particular chemicals for metabolism. The work also has important implications for the devlopment and interpretation of in vitro (or 'test-tube') approaches for predicting how drugs are metabolised in humans. Such tests are widely employed in research and pharmaceutical company laboratories to predict how the body 'handles' new drugs prior to their administration to humans.Read moreRead less
N-glycosylation In Health And Disease: A Key Role For Ost3p And Ost6p In Regulation Of Substrate Specificity.
Funder
National Health and Medical Research Council
Funding Amount
$523,084.00
Summary
Protein glycosylation is the addition of complex sugar chains to specific proteins. Proteins on the surface of cells are often glycosylated, and this is important for controlling the interactions between cells that occur in development, cancer and infection. Glycosylation can be regulated, and our research will characterize the mechanisms of this regulation. This will help us understand exactly how glycosylation is important in cancer and development.
The Molecular Basis Of Cytochrome P450 Ligand Binding: Towards Predicting Enzyme Substrate Selectivity And Drug-drug Interaction Potential
Funder
National Health and Medical Research Council
Funding Amount
$558,447.00
Summary
Cytochrome P450 (CYP) enzymes play a pivotal role in the metabolism (i.e. chemical breakdown) of drugs, a process that is essential for their detoxification and elimination from the body. This project will combine advanced computational and experimental approaches to elucidate the molecular basis for the binding of drugs to CYP enzymes, which is crucial for the design of drugs with favourable metabolic properties and decreased propensity for harmful interactions with co-administered drugs.