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.
Defining The Requirement For The Inhibition Of Bak To The Pathogenesis Of Cytomegalovirus Infection
Funder
National Health and Medical Research Council
Funding Amount
$592,661.00
Summary
Apoptosis, or programmed cell death is a powerful defence mechanism against viral infection. Thus, to replicate efficiently viruses have evolved means to inhibit apoptosis. The central aim of this work is to understand how cytomegalovirus prevents cell death protein during infection. The proposed studies will improve our understanding of the mechanisms that regulate viral replication and will contribute insights into the normal processes that control cell survival.
DNA damage response pathways play important roles in preventing the onset of cancer and regulating the clinical response to chemotherapeutics, and some of the relevant proteins have additional functions during normal development. This fellowship will study new a human protein with key roles in the formation of the lung, and its roles in preventing devastating consequences of normal oxidative damage to DNA, as well as additional fundamental mechanisms involved in preventing genome mutations.
Regulation Of The Drosophila C-Myc Homologue In Stem Cell Growth And Division.
Funder
National Health and Medical Research Council
Funding Amount
$613,397.00
Summary
The mechanisms controlling stem cell growth and division require elucidation if we are to use stem cells in regenerative medicine and find cancer treatments. Due to experimental limitations such mechanisms are largely unknown in humans. We aim to use the vinegar fly as a model system to understand the importance of microenvironment to cancer gene control in stem cells. We will identify the secreted signals, from the neighbouring cells, required to control cancer initiation in stem cells.
Cell death by a specialised process known apoptosis is a way of deleting unwanted and harmful cells from the body. As such, aberrant apoptosis is associated with a wide array of diseases including cancer. For example, abnormal levels of proteins that suppress apoptosis or enhance cell survival can result in cancer and often produce resistance to chemotherapy. To understand and treat cancers that result from aberrant apoptosis we need to know at a molecular level how apoptosis is regulated. Centr ....Cell death by a specialised process known apoptosis is a way of deleting unwanted and harmful cells from the body. As such, aberrant apoptosis is associated with a wide array of diseases including cancer. For example, abnormal levels of proteins that suppress apoptosis or enhance cell survival can result in cancer and often produce resistance to chemotherapy. To understand and treat cancers that result from aberrant apoptosis we need to know at a molecular level how apoptosis is regulated. Central to the apoptosis execution are a group of enzymes called caspases that target many cellular proteins for specific cleavage. In this proposal, we will investigate the function of one of the caspases (called caspase-2), in order to better understand its potential role in the apoptosis of cancer cells. A number of recent reports suggest that caspase-2 levels are reduced in many cancer cells. The human caspase-2 gene localizes to a chromosomal region frequently affected- deleted in leukaemia, and caspase-2 levels have been proposed to be predictors of remission and survival in patients with some types of leukaemia. We will study if loss of caspase-2 in cancer cells makes them resistant to killing by drugs and if mice lacking caspase-2 have an increased potential to develop cancer. Understanding caspase-2 function and its regulation is likely to provide new therapeutic opportunities and potential targets for cancer therapy.Read moreRead less
Characterising The Mechanisms That Control Blood Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$335,616.00
Summary
Hematopoiesis is a tightly regulated process that provides the body with a constant supply of all the cells of the blood system. My studies aim to characterize the molecular mechanisms that regulate the expansion and differentiation of hematopoietic stem cells (HSCs) into each cell lineage. These studies will be key to the effective use of cellular transplantation therapeutic strategies and aim to provide a greater understanding of the mechanisms that underpin proliferative disorders such as can ....Hematopoiesis is a tightly regulated process that provides the body with a constant supply of all the cells of the blood system. My studies aim to characterize the molecular mechanisms that regulate the expansion and differentiation of hematopoietic stem cells (HSCs) into each cell lineage. These studies will be key to the effective use of cellular transplantation therapeutic strategies and aim to provide a greater understanding of the mechanisms that underpin proliferative disorders such as cancer.Read moreRead less
Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and, in ....Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and, in general, to maintain the correct number of cells in the body. As such, misregulation of apoptosis is associated with the pathogenesis of a wide array of diseases. To understand, manage and treat disorders that result from aberrant apoptosis, we need to know at molecular and cellular level, how apoptosis is brought about and how it is regulated. We have been studying these processes in detail for several years. Central to the apoptotic execution of cell death are a group of proteases called caspases, that target many cellular proteins for specific cleavage. The activation of caspases is the crucial step in the initiation of apoptosis and therefore each cell has developed complex ways to control this process. If we understand how these regulatory mechanisms operate, we can then formulate strategies that are targeted towards pathologies involving abnormal apoptosis. In this proposal we will use vinegar fly as a model to study the function of caspases in development. We believe that results from this proposal will have several major benefits. Firstly, they will provide important insight into the mechanisms of developmental apoptosis thereby filling many gaps in our current knowledge. Secondly, the study will endeavour to identify new molecules-pathways that lead to caspase activation. Finally, the proposed studies will shed light on the function of caspases in non-apoptotic pathways.Read moreRead less
Deciphering The Role Of Scribble In Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$628,789.00
Summary
Scribble is a protein that controls the orientation and organization of all cells within our body. Mutations in the Scribble gene are found in many cancers and also in some patients with spina bifida, however how these mutations cause these diseases is not understood. Here we propose experiments that can be used to link Scribble mutations to specific cellular functions. This information will help us design new therapies to treat diseases driven by tissue disorganization such as cancer.
Developing Cancer Therapies That Target Chromosomal Instability
Funder
National Health and Medical Research Council
Funding Amount
$644,126.00
Summary
A significant reason why late-stage cancers are hard to treat with drugs is because the tumour cells show genetic variability, always producing new variants that sooner or later get around the drugs. We intend to combat this by targeting the ability of cancer cells to vary genetically - we are discovering ways to specifically kill genetically unstable cells. This prevents the cancer from developing drug resistance as well as having less side effects on the patient's normal cells.
Australian Drosophila Biomedical Research Support Facility
Funder
National Health and Medical Research Council
Funding Amount
$1,008,895.00
Summary
Breakthroughs in biomedical research frequently come from the study of model organisms, one of the most important of which is the vinegar fly, Drosophila melanogaster. In Australia, Drosophila is used in biomedical research with a particular focus on understanding processes that result in human cancer or are associated with birth defects or inherited diseases. Drosophila-based research is funded by bodies such as the Anti-Cancer Foundation, the National Health and Medical Research Council (NH an ....Breakthroughs in biomedical research frequently come from the study of model organisms, one of the most important of which is the vinegar fly, Drosophila melanogaster. In Australia, Drosophila is used in biomedical research with a particular focus on understanding processes that result in human cancer or are associated with birth defects or inherited diseases. Drosophila-based research is funded by bodies such as the Anti-Cancer Foundation, the National Health and Medical Research Council (NH and MRC) and the National Institutes of Health of the USA. This proposal seeks to establish infrastructure support for Drosophila research in the form of a central collection of key research stocks, a centralized facility for the importation of genetically defined stocks and a facility for the generation of transgenic Drosophila for use in biomedical research.Read moreRead less