I am a cancer biologist investigating mechanisms that regulate the aberrant cell proliferation in cancers, particularly melanomas. I am attempting to utilise defects in normal proliferative mechanisms as targets for novel anti-cancer therapies.
Understanding How RUVBL1 And RUVBL2 Organise Chromosomes And Their Links To Disease
Funder
National Health and Medical Research Council
Funding Amount
$605,005.00
Summary
Our proposal will provide a deep mechanistic framework to inform both clinicians in diagnosis and management of RUVBL related diseases and also therapeutically, as industry looks to use these proteins as drug targets. The great excitement of RUVBL in translation has outpaced the gathering of vital knowledge underpinning the function; knowledge this proposal will provide for the first time.
How Replication Stress Activates The Mitotic Telomere DNA Damage Response To Kill Cancer Cells
Funder
National Health and Medical Research Council
Funding Amount
$486,467.00
Summary
We discovered a novel mechanism linking stress during DNA replication to difficulties with the cell division process, and identified how this turns on DNA damage response signals from the chromosome ends (i.e. “telomeres”). We have further identified that we can exploit this mechanism to kill cancer cells. In this project we will explore this newly discovered mechanism and identify how it can be targeted for therapeutic purposes.
CDK4 Activity In S/G2 Phases Influences Mitotic Fidelity
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
The ultraviolet radiation component of the sunlight is a major environmental factor in the development of skin cancers, including melanomas. Over the past 10 years a genetic factors have also been identified that predispose towards developing melanoma, although the connection between ultraviolet radiation and the genetic factors has remained elusive. In this study we will investigate a cellular mechanism that potentially explains the link between sunlight exposure and one of the genetic risk fac ....The ultraviolet radiation component of the sunlight is a major environmental factor in the development of skin cancers, including melanomas. Over the past 10 years a genetic factors have also been identified that predispose towards developing melanoma, although the connection between ultraviolet radiation and the genetic factors has remained elusive. In this study we will investigate a cellular mechanism that potentially explains the link between sunlight exposure and one of the genetic risk factors. We will also examine whether targeting the pathway this genetic factor normally operates in can deliver increased therapeutic benefit to an existing chemotherapeutic treatment.Read moreRead less
Spatial Arrangement And Three-dimensional Structure Of Human Centromeres
Funder
National Health and Medical Research Council
Funding Amount
$283,000.00
Summary
Centromeres occur at the main constriction of chromosomes. They allow duplicated chromosomes to divide, control cell division and are involved in the control of gene expression. Faulty centromeres are found in many types of cancer and in other genetic diseases. They are also implicated in extra-chromosome disorders such as Down syndrome. Centromeres have a different structure to the rest of the chromosome and it is this structure we wish to study. We want to see how centromere DNA folds up tight ....Centromeres occur at the main constriction of chromosomes. They allow duplicated chromosomes to divide, control cell division and are involved in the control of gene expression. Faulty centromeres are found in many types of cancer and in other genetic diseases. They are also implicated in extra-chromosome disorders such as Down syndrome. Centromeres have a different structure to the rest of the chromosome and it is this structure we wish to study. We want to see how centromere DNA folds up tightly at the centromere. We also want to find out why centromeres locate in certain regions of the nucleus, because this may influence how the centromere works and how they regulate genes. Human centromeres come in many sizes and forms; by looking at a wide range of human centromeres, common structural and spatial properties will emerge. We have discovered very small centromeres - neocentromeres - which are much easier to study than other centromeres. We have used these centromeres to construct human minichromosomes, which we believe represent the main, all-human way forward to treat people with gene therapy. One way to help us achieve our aims is to stretch out centromeres in a controlled way to make it easier to visualise their structure. Our tools will be antibodies, fluorescently-labelled proteins and high resolution microscopes. These include an electron microscope, and microscopes that can produce optical sections and in turn a 3D image. One of these is the confocal laser scanning microscope; the other involves removal of out-of-focus light from images using deconvolution software to achieve the same goal. We will detect different centromere proteins with different fluorochromes for fluorescence microscopes and different sizes of gold particles for the electron microscope. Using these microscopes we have already been able to find out where one of our neocentromeres is located within the nucleus. We have also started to look at centromeres with the electron microscope.Read moreRead less
HFP ACTIVATES PROTEOLYSIS OF POSITIVE CELL CYCLE REGULATORS TO INHIBIT CELL CYCLE PROGRESSION IN DROSOPHILA
Funder
National Health and Medical Research Council
Funding Amount
$438,750.00
Summary
Cell proliferation is essential for animal development and tissue regeneration. In order to proliferate, cells must double their DNA contents and segregate their chromosomes precisely into daughter cells. Collectively this series of events is referred to as the Cell Cycle. The cell cycle must be carefully regulated since inappropriate proliferation can cause developmental abnormalities and tumour formation in multicellular animals. Proliferation is regulated by a balanced set of interactions bet ....Cell proliferation is essential for animal development and tissue regeneration. In order to proliferate, cells must double their DNA contents and segregate their chromosomes precisely into daughter cells. Collectively this series of events is referred to as the Cell Cycle. The cell cycle must be carefully regulated since inappropriate proliferation can cause developmental abnormalities and tumour formation in multicellular animals. Proliferation is regulated by a balanced set of interactions between two group of proteins, cell cycle activators and cell cycle inhibitors. Aberrations in cell cycle inhibitor proteins will cause excessive cell proliferation, the first step in the multi-step process of tumour development. It is important to understand the processes that normally inhibit cell proliferation, since cells undergoing more rapid cell cycles are much more likely to develop further errors in their genetic material and progress to later stage invasive tumours. This proposal focuses on a protein (FIR-Hfp) that we have shown to inhibit cell cycle progression in the vinegar fly (Drosophila Melanogaster), which is an excellent model organism for studying developmentally regulated cell proliferation. Furthermore, most cell cycle regulators are conserved in evolution, so the knowledge derived from these studies can assist with our understanding of how complex pathways might coordinate proliferation mammals. FIR-Hfp negatively regulates cell proliferation by down-regulating cycle activator proteins (dMyc and Stg). At present the mechanism for the inhibitory affect on these activators is not understood, but preliminary data suggests that FIR-Hfp might be involved in causing Stg and the dMyc activator protein (Hay) to be targeted for destruction. The aim of this project is to elucidate the mechanism by which Hfp regulates the activity of these potentially ocogenic factors, and thus gain a better understanding of the preliminary stages of tumour progression.Read moreRead less