Molecular Characterisation Of A New Survival Pathway In Haematopoietic Cells
Funder
National Health and Medical Research Council
Funding Amount
$571,631.00
Summary
It is critical for normal health that cells regulate their responses to changes in the the extracellular environment. Receptors on the cell surface are triggered by specific proteins called cytokines, and relay information to the cell interior. These messages include signaling whether cells should survive and proliferate. Inappropriate activation of signals for survival and proliferation is a hallmark of cancer. We are investigating a new survival signal and how this contributes to the survival ....It is critical for normal health that cells regulate their responses to changes in the the extracellular environment. Receptors on the cell surface are triggered by specific proteins called cytokines, and relay information to the cell interior. These messages include signaling whether cells should survive and proliferate. Inappropriate activation of signals for survival and proliferation is a hallmark of cancer. We are investigating a new survival signal and how this contributes to the survival of normal cells and to diseases such as leukaemia.Read moreRead less
In a human body, about a million cells are born every second, and a million die by activating a physiological cell death mechanism. If cell death fails to occur, cells accumulate and can develop into cancers. Determining the mechanism and regulation of physiological cell death will provide novel approaches to treat cancers and auto-immune diseases, both of which are characterised by failure of certain cells to die.
Characterization Of Novel Inhibitors Of G1-S Phase Progression In Drosophila
Funder
National Health and Medical Research Council
Funding Amount
$456,000.00
Summary
Cancer is a disease that affects 1-3 people and therefore, understanding the mechanisms by which cancer arises is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in the regulation of cell p ....Cancer is a disease that affects 1-3 people and therefore, understanding the mechanisms by which cancer arises is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in the regulation of cell proliferation, and have been studying this in the genetically amenable animal model system, the vinegar fly, Drosophila. A key regulator of cell proliferation in all multicellular organisms is Cyclin E, which is required to drive cells from the G1 (resting state) into S phase (where DNA replication occurs). Correct control of Cyclin E is important in limiting cell proliferation and many cancer-causing mutations result in up-regulation of this critical cell cycle regulator. We have used a genetic approach to identify novel negative regulators of Cyclin E. This proposal seeks to further clarify the mechanism by which the identified Cyclin E interactors regulate cell cycle progression. In addition, this proposal seeks to identify the genes encoding other cyclin E interactors, expected to be novel tumor suppressors. The expected outcome of this project is to elucidate novel genes and mechanisms that control cell proliferation in the context of a whole organism. Due to the conservation of cell proliferation and signalling proteins, this proposal is relevant to understanding human cancer.Read moreRead less
Regulation And Mechanisms Of Cell Cycling, Cell Senescence And Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$876,005.00
Summary
Most of our cells are not dividing, but persist in a stable arrested state, yet little is known of the molecular mechanisms that regulate and maintain permanent arrest, or that go wrong when cells start proliferating and turn into cancers. This proposal addresses an area of fundamental, basic biology, that has been largely overlooked. A better understanding of the molecules that regulate cell stability might provide new drug targets so that tumour cell proliferation can be stopped.
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.
Exploring The Inflammatory Signature Of The Anti-cancer Smac-mimetic, Birinapant, And The Contribution Of This Signature To Birinapant Anti-Tumour Activity
Funder
National Health and Medical Research Council
Funding Amount
$192,322.00
Summary
Programmed cell death (PCD) is an essential process for the removal of cancer cells. Defects in PCD are now known to be a causal factor in cancer initiation and chemotherapeutic resistance. Proteins called IAPs protect cancer cells from PCD, however, inhibitors of IAPs have been developed to kill cancer cells in this respect. Indeed, IAP inhibitors can also promote inflammation, which may improve or hamper their efficacy in killing cancer cells, an issue we now wish to explore and exploit.
Regulation Of Mesenchymal To Epithelial Transitions By Netrin Receptors
Funder
National Health and Medical Research Council
Funding Amount
$646,995.00
Summary
The formation of 2D cellular sheets is important during development, tissue repair, and tumor growth. The mechanisms involved, however, remain largely unknown. Recent findings in the fly and in human cells suggest Frazzled/Neogenin receptors drive this process, by establishing polarised scaffolds in the cell. We will test this hypothesis using fly genetics and analysis of 3-dimensional culture of mammalian cells. Our results will help guide future therapies for human disease.
Hormone-dependent Autophagy And Growth Signalling In Developmental Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$613,447.00
Summary
Cell death is essential for cell and tissue homeostasis and its dysregulation is associated with many diseases. We discovered a new mode of cell death that involves autophagy. We have now identified that TGF-? signalling pathway, which has roles in numerous human pathologies, is involved in autophagy-dependent cell death. Our proposed studies will further characterise this important signalling axis and study its significance in development, normal physiology and disease.
Examination Of The Mechanism By Which The Salvador/warts/hippo Complex Restricts Cell Growth And Number
Funder
National Health and Medical Research Council
Funding Amount
$283,767.00
Summary
Cancer is a disease that results from the generation of surplus cells. These extra unwanted cells are produced as a result of excess cell proliferation and impaired programmed cell death. These important processes can be deregulated in cancers as a result of mutations in many different genes. Many genetic lesions have been reported in different types of cancers but many of the genes that are mutated in these diseases have yet to be identified. To isolate new genes involved in cancer we created r ....Cancer is a disease that results from the generation of surplus cells. These extra unwanted cells are produced as a result of excess cell proliferation and impaired programmed cell death. These important processes can be deregulated in cancers as a result of mutations in many different genes. Many genetic lesions have been reported in different types of cancers but many of the genes that are mutated in these diseases have yet to be identified. To isolate new genes involved in cancer we created random mutations in the vinegar fly, Drosophila, and tested their ability to cause solid cancers. Drosophila is an excellent model organism for this study because many of the pathways that are often perturbed in cancer are conserved between humans and flies. Using this approach we identified several known and novel genes that cause cancerous growths. By studying the human counterparts of these novel genes we identified a potential role for some of these genes in the generation of human cancer. Three of these genes, hippo, salvador and warts, appear to act in concert to restrict cell number. In this study we aim to understand the mechanism by which these genes restrict cell number. To do this we will analyze how the activity of this pathway is controlled and in what tissues it functions. We also plan to discover other key components of this pathway that function downstream of hippo, salvador and warts. To perform these experiments we will use a variety in vitro biochemical techniques as well as experiments in tissue culture cells. We will then verify the results of these experiments in the context of a whole animal. By performing these experiments we hope to gain greater insight into the genesis of cancer.Read moreRead less