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Temporal And Spatial Regulation Of Caspases In Development And Metamorphosis
Funder
National Health and Medical Research Council
Funding Amount
$473,250.00
Summary
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 g ....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, misregulated apoptosis is associated with the pathogenesis of a wide array of diseases such as autoimmune diseases, many forms of cancer and neurodegenerative disorders (such as Alzheimer's and Parkinson's diseases), heart disease, ischaemia and other conditions. 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 that target many cellular proteins for specific cleavage. The activation of these proteases is the crucial step in the initiation of apoptosis and therefore each cell has developed complex ways to control this process. In the present proposal, we aim to study regulation of caspases that are involved in developmental apoptosis. Furthermore, we plan to identify proteins that are responsible for the regulation of caspase activation.Read moreRead less
Regulation Of Nuclear Calcium Concentration In The Life Or Death Of Cells
Funder
National Health and Medical Research Council
Funding Amount
$195,047.00
Summary
The nucleus is the most prominent of all cell organelles and contains the primary genetic material for cellular development and growth. It performs some of the most important functions in the life and death of all living cells. However, little is known about many of the regulatory signals and events that control nuclear function. We will use new genetically-encoded sensor molecules that a living cell can be instructed to produce at various internal locations to explore important features of cell ....The nucleus is the most prominent of all cell organelles and contains the primary genetic material for cellular development and growth. It performs some of the most important functions in the life and death of all living cells. However, little is known about many of the regulatory signals and events that control nuclear function. We will use new genetically-encoded sensor molecules that a living cell can be instructed to produce at various internal locations to explore important features of cell control. This study will look specifically at how changes in the concentration of ionised Ca2+ in the nucleus control the switching on of genes and the initiation of programmed cell death pathways. This information is of significance to our understanding of normal cell growth and development, as well as abnormal growth (e.g. cancer).Read moreRead less
Characterisation Of The Anti-apoptotic Function Of P-glycoprotein And Transcriptional Regulation Of The MDR1 Gene
Funder
National Health and Medical Research Council
Funding Amount
$324,150.00
Summary
The ability of tumor cells to survive treatment by chemotherapy is a major obstacle in curing patients with cancer. One mechanism by which cancer cells become multidrug resistant (MDR) is their acquired expression of a cell surface protein called P-glycoprotein (P-gp) that serves to extrude cytotoxic drugs out of the cancer cell via a pumping mechanism. Recently, we demonstrated, that in addition to its role in removing drugs from cells, P-gp can also protect cells against death induced by stimu ....The ability of tumor cells to survive treatment by chemotherapy is a major obstacle in curing patients with cancer. One mechanism by which cancer cells become multidrug resistant (MDR) is their acquired expression of a cell surface protein called P-glycoprotein (P-gp) that serves to extrude cytotoxic drugs out of the cancer cell via a pumping mechanism. Recently, we demonstrated, that in addition to its role in removing drugs from cells, P-gp can also protect cells against death induced by stimuli other than drugs where an efflux effect of P-gp would have no obvious benefit. This broader effect of P-gp to enhance cell survival may be explained by its ability to regulate the activity of key enzymes that exist within cells to induce cell suicide when appropriate. Some chemotherapeutic drugs activate these death enzymes (caspases) to kill target cells and it is therefore possible that P-gp affects the activity of anti-cancer drugs by both removing the drugs from the target cells and inhibiting the pathways through which the drugs can kill the cell. We are now determining how P-gp affects the activity of caspases. In addition, we have defined the manner by which P-gp expression is kept low in normal cells and is upregulated in many MDR tumor cells. It appears that the way the gene expressing P-gp (called MDR1) is packaged within chromosomes regulates gene expression levels. We are now identifying the proteins and complexes involved in regulating MDR1 expression to fully determine the molecular events that occur during the manifestation of a P-gp-expressing MDR tumor. Our new findings may lead to novel treatment options for patients that have MDR cancers and may provide insight into possible new ways to inhibit the formation of P-gp-expressing MDR tumors in the first place.Read moreRead less
Regulation Of Cell Death And Proliferation By Histone Demethylases
Funder
National Health and Medical Research Council
Funding Amount
$521,105.00
Summary
Turning genes 'on' and 'off' is essential for normal functioning of cells in the body. Modifications to chromatin (DNA-protein complexes that make up the chromosomes) by some enzymes regulate this switch. This project will identify enzymes that modulate chromatin to control gene expression during cell death and proliferation to maintain cell homeostasis. The study of these enzymes will be important in better understanding of cancer development and in discovering new targets for cancer therapy.
Spatial And Temporal Aspects Of Epigenetic Remodelling In Cancer
Funder
National Health and Medical Research Council
Funding Amount
$626,707.00
Summary
Epigenetic deregulation occurs commonly in cancer, and can affect not only single genes but can encompass large chromosomal domains, leading to altered expression of oncogenes and tumour suppressor genes, and genomic instability. We will investigate the role of epigenetic remodeling, how spacial reorganisation of the genome, nuclear architecture, chromatin looping and replication timing may affect long range epigenetic deregulation, and ultimately contribute to cancer formation and progression.
An Alternate Function Of The MicroRNA Biogenesis Machinery
Funder
National Health and Medical Research Council
Funding Amount
$302,981.00
Summary
Controlling the activity of genes is crucial. Too much or too little can result in a cell not functioning properly. We have discovered a new way genes are controlled. We have found that an enzyme called Drosha can prevent too much activation of some genes by chopping up the products of these genes. This way of controlling genes appears to be especially important for developmental processes, such as occurs in the embryo. Our goal is to understand this mechanism precisely at the molecular level.
Understanding The Mechanism Of Action And Pathophysiological Function Of The NOR1 And Nur77 Orphan Nuclear Receptors
Funder
National Health and Medical Research Council
Funding Amount
$269,250.00
Summary
Nuclear hormone receptors (NRs) function as ligand-hormone activated transcription factors that regulate gene expression involved in reproduction, development and metabolism. Dysfunctional hormonal signalling, and inappropriate NR function results in reproductive disorders, inflammation, cancer, diabetes, and cardiovascular disease. The significance of NRs in disease is underscored by the range of pharmacopoeia developed for the treatment of NR associated disorders. Orphan NRs belong to the supe ....Nuclear hormone receptors (NRs) function as ligand-hormone activated transcription factors that regulate gene expression involved in reproduction, development and metabolism. Dysfunctional hormonal signalling, and inappropriate NR function results in reproductive disorders, inflammation, cancer, diabetes, and cardiovascular disease. The significance of NRs in disease is underscored by the range of pharmacopoeia developed for the treatment of NR associated disorders. Orphan NRs belong to the superfamily on the basis of their sequence identity, however, the endogenous signaling molecules which bind to these proteins are unknown. The orphan NRs Nur77, NURR1, and NOR1, functions as stress response genes which are induced by a wide range of physiological stimuli Furthermore, the NR4A subgroup of receptors has been implicated in carcinogenesis, neurological disorders; inflammation, diabetes and atherogenesis. The objective of this proposal is to examine the molecular mechanisms that control the regulation of gene expression by the orphan nuclear receptors, Nur77 and NOR-1. Furthermore, we will investigate the pathophysiological function of NOR-1 and Nur77 in muscle. Nur77 and NOR-1 are expressed in skeletal muscle. This major mass tissue accounts for ~40% of total body weight and, is a major site of glucose and fat metabolism. Consequently, this peripheral tissue plays a significant role in insulin sensitivity, and the blood lipid profile. Furthermore, a collaboration with industry has identified NOR-1 as an insulin responsive gene in muscle, which becomes hyper-sensitive to insulin induction in diabetic patients. Additionally, we have exciting evidence that the anti-neoplastic purine anti-metabolite, 6-mercaptopurine activates the NR4A subgroup. Nur77 and NOR-1 represent an exciting challenge, and unlocking the molecular mechanisms that NOR-1-dependent transcription provides the opportunity for identifying novel signaling pathways, and therapeutics.Read moreRead less
Role Of Immediate Early Gene Induction And AP-1 Activation In HDAC Inhibitor Induced Apoptosis.
Funder
National Health and Medical Research Council
Funding Amount
$524,820.00
Summary
Histone deacetylase inhibitors (HDACi) are a novel class of anti-tumor agents, recently approved for the treatment of cutaneous T-cell lymphoma. The goal of this study is to improve our understanding of how this class of drug induces tumor cell death. These studies are designed to provide insight into which patients are most likely to benefit from treatment with these agents. Second, they will provide direction into how the therapeutic efficacy of HDACi may be enhanced, through combination with ....Histone deacetylase inhibitors (HDACi) are a novel class of anti-tumor agents, recently approved for the treatment of cutaneous T-cell lymphoma. The goal of this study is to improve our understanding of how this class of drug induces tumor cell death. These studies are designed to provide insight into which patients are most likely to benefit from treatment with these agents. Second, they will provide direction into how the therapeutic efficacy of HDACi may be enhanced, through combination with other existing therapeutics.Read moreRead less