The Polycomb Ezh2 Methyltransferase Regulates Satellite Cell Self-renewal
Funder
National Health and Medical Research Council
Funding Amount
$333,769.00
Summary
Skeletal muscle regeneration following injury is a tightly regulated process and any disturbance to this process, such as that which occurs with the muscular dystrophies, can greatly impair a muscle's ability to regenerate. The aim of this project is to better understand the mechanisms that control muscle regeneration, and open up new avenues for potential treatment strategies in conditions where muscle wasting and weakness are indicated.
The Role Of The MYST Family Transcriptional Co-activator, Mof, In Embryonic Development
Funder
National Health and Medical Research Council
Funding Amount
$319,446.00
Summary
A major task in biology is to understand how the human genome directs the development of a single cell to form an entire individual. Clearly, a large part of this task is to understand how the expression of genes is regulated during embryonic development. Gene expression requires co-activator complexes. Co-activator complexes typically contain proteins which regulate the structure of chromatin (a complex of DNA and histones). However, the physiological function of most co-activators is entirely ....A major task in biology is to understand how the human genome directs the development of a single cell to form an entire individual. Clearly, a large part of this task is to understand how the expression of genes is regulated during embryonic development. Gene expression requires co-activator complexes. Co-activator complexes typically contain proteins which regulate the structure of chromatin (a complex of DNA and histones). However, the physiological function of most co-activators is entirely unclear. The aim of this project is to study the function of Mof during embryonic development. Mof is a co-activator that directly regulates chromatin structure by modifying histones. Mof is a member of the MYST family of co activators, which includes Moz and Qkf. We have recently shown that Moz and Qkf are essential for the haematopoietic stem cell population and the neural stem cell population, respectively. The purpose of this project is to produce a detailed analysis of the function of Mof in vivo and determine it's importance in regulating gene expression. All biological processes relay on accurate regulation of gene transcription and all diseases, whether they involve pathogens or cell intrinsic pathological changes, such as cancer, lead to changes in gene expression. Regulation of chromatin structure has been identified as a major mechanism of transcriptional regulation in health and disease. However, our understanding of the precise molecular mechanisms regulating chromatin structure in vivo are very limited. This work will fully investigate the role of an important co-activator in vivo including a mechanistic analysis. This will increase understanding of how gene expression is regulated and, ultimately, this knowledge will find wide application in the development of new treatment paradigms.Read moreRead less
The Role Of Centromere Proteins In Centromere Assembly, Chromosome Instability, And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$687,750.00
Summary
Our genetic information are organised into compact structures known as chromosomes in our cells. Each human cell has 46 chromosomes. Excess or insufficient copies of these chromosomes will cause genetic imbalance that often results in serious clinical problems such as Down syndrome, cancer, embryonic death, and a host of other syndromes. The study of the process of how the exact number of chromosomes is distributed amongst daughter cells when cells divide is therefore an important area of resear ....Our genetic information are organised into compact structures known as chromosomes in our cells. Each human cell has 46 chromosomes. Excess or insufficient copies of these chromosomes will cause genetic imbalance that often results in serious clinical problems such as Down syndrome, cancer, embryonic death, and a host of other syndromes. The study of the process of how the exact number of chromosomes is distributed amongst daughter cells when cells divide is therefore an important area of research. Our laboratory has focused research on a key structure of the chromosome known as the centromere that determines how this process is controlled. The present project aims to study the properties of the centromere in detail using the technique of targeted gene mutation in mice. In these mice, the functions of individual genes that make specific centromere proteins are destroyed or modified through a precisely controlled mutation process. The effects such mutations have on the development of the animals and on chromosome division can then be analysed in great detail. The outcome will be a significant increase in our understanding of the functions of the different centromere proteins, an understanding that is key to the further advancement of our knowledge on the aetiology of some of the most frequently seen disease conditions in humans, including 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