The Role Of Proteinase Inhibitor 9 In Cytotoxic Lymphocyte Function
Funder
National Health and Medical Research Council
Funding Amount
$820,136.00
Summary
Cytotoxic lymphocytes eliminate virus-infected or cancerous cells from the body. This is achieved by the release of powerful cytotoxins that kill the abnormal cell. Unless carefully targeted these cytotoxins can damage surrounding normal tissue or the cytotoxic lymphocyte itself, and lead to autoimmune disease. One of the most important cytotoxins is a protease called granzyme B. We have discovered a natural inhibitor of granzyme B that is present in cytotoxic cells and testis. Our studies are a ....Cytotoxic lymphocytes eliminate virus-infected or cancerous cells from the body. This is achieved by the release of powerful cytotoxins that kill the abnormal cell. Unless carefully targeted these cytotoxins can damage surrounding normal tissue or the cytotoxic lymphocyte itself, and lead to autoimmune disease. One of the most important cytotoxins is a protease called granzyme B. We have discovered a natural inhibitor of granzyme B that is present in cytotoxic cells and testis. Our studies are aimed at understanding the role of the inhibitor in human immune and reproductive function. We will also design and evaluate synthetic compounds based on the natural inhibitor that will enable us to easily measure granzyme B levels and control its activity.Read moreRead less
Studies in humans and model organisms have shown that defects in centromere function result in chromosome abnormalities and copy-number changes that constitute a major cause of aneuploid-related syndromic disorders, intellectual disability, infertility, pregnancy loss, and cancer. Understanding the biological properties and functions of the centromere is therefore a high priority for health research.
Chromosomes are structures that carry genes in all our cells. Every human cell has 46 chromosomes. In the nucleus of eukaryotic cells, DNA is highly folded and compacted with specific proteins into a dynamic polymer called chromatin. Gene expression, chromosome division, DNA replication, and repair all act, not on DNA alone, but on this chromatin template. The discovery that enzymes can (re)organise chromatin into accessible and inaccessible configurations revealed mechanisms that considerably e ....Chromosomes are structures that carry genes in all our cells. Every human cell has 46 chromosomes. In the nucleus of eukaryotic cells, DNA is highly folded and compacted with specific proteins into a dynamic polymer called chromatin. Gene expression, chromosome division, DNA replication, and repair all act, not on DNA alone, but on this chromatin template. The discovery that enzymes can (re)organise chromatin into accessible and inaccessible configurations revealed mechanisms that considerably extend the information potential of the genetic code. In addition, it is now established that chromatin structural features can influence gene expression. In vitro studies support a model in which chromatin functions as a barrier for the access to DNA. Therefore this organization has to be tighly regulated and dynamic to allow the protein-DNA interactions critical for nuclear functions. Importantly genome organisation provides in addition to genetic information another layer of information, so called epigenetic, which by definition means that it is stably inherited throughout cellular divisions, yet it is not encoded genetically. Thus each cell type will display a specific epigenome. We have recently constructed small human minichromosomes, which are much easier to study than the much larger normal chromosomes. The present project proposes to define the epigenetic feature across an entire human chromosome using our minichhromosomes as working models. The outcome will be a significant gain in our knowledge on the processes underlying epigenetic regulation, the organisation of specialised chromatin domain, and behaviour of the chromosomes.Read moreRead less
The Role Of Oocyte-secreted Proteins In Primate Follicular Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$176,320.00
Summary
Mammalian eggs grow and develop in fluid filled sacks in the ovary called follicles. These structures nurture the egg for prolonged periods preparing it for ovulation and fertilisation. It has been known for some time that the quality of the follicular environment determines, in part, the developmental potential of the egg. Recent studies in mice have shown that the interaction between the egg and the follicle is in fact a two-way process, and that the egg is able to influence development of the ....Mammalian eggs grow and develop in fluid filled sacks in the ovary called follicles. These structures nurture the egg for prolonged periods preparing it for ovulation and fertilisation. It has been known for some time that the quality of the follicular environment determines, in part, the developmental potential of the egg. Recent studies in mice have shown that the interaction between the egg and the follicle is in fact a two-way process, and that the egg is able to influence development of the follicle. This project proposes to investigate these processes further in the laboratory mouse using new reagents available to us, and to extend these findings by investigating this communication pathway for the first time in a primate species. Because of the difficulty of undertaking such research using human material, we will use the marmoset monkey as a model. This exciting new development has important implications for women's health because it may help us understand why some women suffer from premature menopause or cystic ovaries, and in the longer term could help in the development of new types of contraceptives.Read moreRead less