Regulation Of Tissue-type Plasminogen Activator Gene Expression In Endothelial Cells And In Transgenic Mice
Funder
National Health and Medical Research Council
Funding Amount
$244,009.00
Summary
Tissue-type plasminogen activator (t-PA) is an enzyme which plays an important role in the removal of blood clots from the circulation. One of the major sites of production of t-PA are endothelial cells which line the blood vessel wall. The rate of t-PA production is greatly influenced by factors released from other cells. One of these factors is tumour necrosis factor (TNF). The t-PA gene is switched off in endothelial cells exposed to TNF. One of the aims of this project is to understand how t ....Tissue-type plasminogen activator (t-PA) is an enzyme which plays an important role in the removal of blood clots from the circulation. One of the major sites of production of t-PA are endothelial cells which line the blood vessel wall. The rate of t-PA production is greatly influenced by factors released from other cells. One of these factors is tumour necrosis factor (TNF). The t-PA gene is switched off in endothelial cells exposed to TNF. One of the aims of this project is to understand how the t-PA gene is suppressed by TNF in human endothelial cells and in transgenic mice. The transgenic mice we have available express the regulatory region of the t-PA gene (called the gene promoter) connected to a reporter gene called LacZ. We will use these animals to visualise the expression pattern of LacZ expression under normal conditions and in mice treated with TNF. The results of these experiments will provide new information as to how the t-PA gene is controlled in cells and in the body.Read moreRead less
Identification Of Critical Regulatory Elements In The BRCA1 Gene
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Breast cancer affects approximately one in ten women and is therefore a major health problem. In order to improve the diagnosis, treatment and prognosis of this disease, it is critical to understand the molecular defects that contribute to disease initiation and progression. Over the last twenty years significant progress has been made in this regard, however there still remain a considerable number of unanswered questions. For example, it is not yet clear precisely what contribution each of the ....Breast cancer affects approximately one in ten women and is therefore a major health problem. In order to improve the diagnosis, treatment and prognosis of this disease, it is critical to understand the molecular defects that contribute to disease initiation and progression. Over the last twenty years significant progress has been made in this regard, however there still remain a considerable number of unanswered questions. For example, it is not yet clear precisely what contribution each of these genes makes. This is largely due to limitations in current mutation detection strategies and an incomplete understanding of all of the genetic elements for which disruption can lead to loss of gene function. This propsal aims to identify all of the genetic elements critical for the expression of an important breast cancer gene called BRCA1. Furthermore, it aims to determine the status of these elements in breast cancer patients, thus expanding our knowledge of the actual contribution disruption of this gene makes to this disease.Read moreRead less
Analysis Of Very Early Cancer-related Methylation Abnomalities
Funder
National Health and Medical Research Council
Funding Amount
$422,310.00
Summary
The factors that are involved in triggering cancer are still unknown. Increasing evidence however indicates that the DNA in the pre-cancer cell becomes modified leading to altered expression of important genes called tumour suppressor genes. Often the DNA is deleted or mutated but it can also become chemically changed by a process called DNA methylation. We have found that an important tumour suppressor gene called p16 is inactivated and chemically methylated in breast epithelial cells at the st ....The factors that are involved in triggering cancer are still unknown. Increasing evidence however indicates that the DNA in the pre-cancer cell becomes modified leading to altered expression of important genes called tumour suppressor genes. Often the DNA is deleted or mutated but it can also become chemically changed by a process called DNA methylation. We have found that an important tumour suppressor gene called p16 is inactivated and chemically methylated in breast epithelial cells at the stage when the cell changes to a pre-cancer cell. This grant is aimed at finding what triggers the silencing and methylation of the p16 gene in this early pre-cancer stage. We also plan to identify other genes are methylated and undergo inactivation the pre-cancer breast cells. These results will have an impact on understanding the molecular mechanism that makes a breast cell susceptible to cancer and may lead to insights into new prevention and treatment strategies.Read moreRead less
Oxidative Damage and Cell Ageing. This research will benefit Australia by providing a fundamental understanding of how cells age. This will have immediate international impact at the scientific level and will inform strategies to reduce the rate of ageing and alleviation of age-related disorders. In the longer term the research may provide commercial and social outcomes by identifying antioxidant systems that will provide a genuine benefit in reducing ageing.
Cellular Responses to Oxidative Damage: Cell Aging. The aim of this project is to identify the mechanisms by which oxidative stress and free radical damage cause cell aging. This work will make a significant contribution to our understanding of the aging process in cells by identifying the major reactive oxygen species that contribute to cell aging, which defence systems and antioxidants provide the greatest degree of protection, what damage accumulates as cells age and which genetic systems ar ....Cellular Responses to Oxidative Damage: Cell Aging. The aim of this project is to identify the mechanisms by which oxidative stress and free radical damage cause cell aging. This work will make a significant contribution to our understanding of the aging process in cells by identifying the major reactive oxygen species that contribute to cell aging, which defence systems and antioxidants provide the greatest degree of protection, what damage accumulates as cells age and which genetic systems are activated as during the process.Read moreRead less
CesA (cellulose synthase) genes of Arabidopsis; all doing the same job or specialists cooperating to make the most abundant biopolymer. The biosphere makes more cellulose than any other polymer with fibre industries depending on its physical properties and atmospheric carbon dioxide levels depending on its stability as a carbon sink. Demonstrations that cellulose production needs CesA genes drove recent progress in elucidating the mechanism of synthesis. CesA proteins all look very similar but i ....CesA (cellulose synthase) genes of Arabidopsis; all doing the same job or specialists cooperating to make the most abundant biopolymer. The biosphere makes more cellulose than any other polymer with fibre industries depending on its physical properties and atmospheric carbon dioxide levels depending on its stability as a carbon sink. Demonstrations that cellulose production needs CesA genes drove recent progress in elucidating the mechanism of synthesis. CesA proteins all look very similar but if all do the same job, why do plants need so many and why do none seem redundant? We will make gene interchanges in transgenic plants, build chimeric genes and identify where each CesA protein operates. This will identify their individual and cooperative contributions to cellulose production.Read moreRead less
Function of a new splicing factor, RBM4. New genomic knowledge is revolutionizing our world. However our understanding of the basic mechanisms of RNA maturation, especially regulation of splicing lags significantly behind our understanding of related genomic processes. This project is a genetic approach to help elucidate the function of new splicing factors and characterize the way in which specific RNA sequences are recognized. It should promote the better understanding of regulatory events inv ....Function of a new splicing factor, RBM4. New genomic knowledge is revolutionizing our world. However our understanding of the basic mechanisms of RNA maturation, especially regulation of splicing lags significantly behind our understanding of related genomic processes. This project is a genetic approach to help elucidate the function of new splicing factors and characterize the way in which specific RNA sequences are recognized. It should promote the better understanding of regulatory events involved in controlling gene expression during development and differentiation. Results from this project will also provide new insights into the 'multifunctionality' of cellular proteins and will illustrate the importance of RNA studies in molecular medicine.Read moreRead less