This is a study of the biological system of epigenetics. Every cell in our body has the same genetics, or library of information contained in the form of DNA sequence. Epigenetics is the system that controls how this DNA is used in a particular situation, or what books are opened and read. During embryonic development, cells know what they want to become, e.g., a muscle cell, and, once they take on an identity, remember that they are when they duplicate themselves during growth. Epigenetics does ....This is a study of the biological system of epigenetics. Every cell in our body has the same genetics, or library of information contained in the form of DNA sequence. Epigenetics is the system that controls how this DNA is used in a particular situation, or what books are opened and read. During embryonic development, cells know what they want to become, e.g., a muscle cell, and, once they take on an identity, remember that they are when they duplicate themselves during growth. Epigenetics does not achieve this through changing genetics the library always stays intact. Rather, it acts by using proteins or chemicals to make DNA functional in one way, or another. Genomic imprinting is a special type of epigenetics. While an embryo has received identical genetic information from each of its parents, the epigenetic information received from each parent was not entirely the same. Some genes which behave differently according to what parent they came from. For example, a gene that makes a growth factor protein is active only if received from the father. If received from the mother, it is inactive, and makes no protein. Genes behaving in this way are known as imprinted genes. We are trying to discover what epigenetic mechanisms are behind this behaviour of imprinted genes. One way we are approaching this problem is to study germ cells the cells giving rise to eggs and sperm. These cells are unusual in that their imprinted genes behave in the same way regardless of whether they were received from the mother or father, i.e., like any other gene. If we can understand why this is the case, we will be better able to understand why imprinted genes behave the way they do in the rest of the cells of the body. Broadly, the mechanisms we uncover should further our understanding of germ cell development, gene expression, and disease. Perturbations in the epigenetic profile are likely causes of human disease, including cancer.Read moreRead less
This is a study of the biological system of epigenetics. Every cell in our body has the same genetics, or library of information contained in the form of DNA sequence. Epigenetics is the system that controls how this DNA is used in a particular situation, or what books are opened and read. During embryonic development, cells know what they want to become, e.g., a muscle cell, and, once they take on an identity, remember that they are when they duplicate themselves during growth. Epigenetics does ....This is a study of the biological system of epigenetics. Every cell in our body has the same genetics, or library of information contained in the form of DNA sequence. Epigenetics is the system that controls how this DNA is used in a particular situation, or what books are opened and read. During embryonic development, cells know what they want to become, e.g., a muscle cell, and, once they take on an identity, remember that they are when they duplicate themselves during growth. Epigenetics does not achieve this through changing genetics - the library always stays intact. Rather, it acts by using proteins or chemicals to make DNA functional in one way, or another. Genomic imprinting is a special type of epigenetics. While an embryo has received identical genetic information from each of its parents, the epigenetic information received from each parent was not entirely the same. Some genes which behave differently according to what parent they came from. For example, a gene that makes a growth factor protein is active only if received from the father. If received from the mother, it is inactive, and makes no protein. Genes behaving in this way are known as imprinted genes. We are trying to discover what epigenetic mechanisms are behind this behaviour of imprinted genes. One way we are approaching this problem is to study germ cells - the cells giving rise to eggs and sperm. These cells are unusual in that their imprinted genes behave in the same way regardless of whether they were received from the mother or father, i.e., like any other gene. If we can understand why this is the case, we will be better able to understand why imprinted genes behave the way they do in the rest of the cells of the body. Broadly, the mechanisms we uncover should further our understanding of germ cell development, gene expression, and disease. Perturbations in the epigenetic profile are likely causes of human disease, including cancer.Read moreRead less
The Regulation Of Pluripotency And Self-renewal In Embryonic And Germline Stem Cells.
Funder
National Health and Medical Research Council
Funding Amount
$491,767.00
Summary
Regulation of self-renewal and developmental potential in embryonic and germline stem cells. The capacity of some stem cells to self-renew and under specific conditions, give rise to all adult cell types, a property known as pluripotency , is the key to unlocking the potential of cell based therapies. The development of stem cell based therapies promises to revolutionize the treatment of many common human diseases. For instance, in neurodegenerative conditions such as Parkinsons disease, normal ....Regulation of self-renewal and developmental potential in embryonic and germline stem cells. The capacity of some stem cells to self-renew and under specific conditions, give rise to all adult cell types, a property known as pluripotency , is the key to unlocking the potential of cell based therapies. The development of stem cell based therapies promises to revolutionize the treatment of many common human diseases. For instance, in neurodegenerative conditions such as Parkinsons disease, normal embryonic stem cells grown in culture could be used to replace the lost or disabled neurons in the patient. Many other conditions including diabetes, cystic fibrosis, myocardial infarction (heart attack) and stroke could potentially be treated with stem cell based therapies. Understanding the molecular regulators that govern establishment and maintenance in culture of stem cell lines derived from embryos and from germ cells is the primary goal of this study. We will use well-established techniques to genetically manipulate mouse embryonic stem cells and embryos to examine the role of a specific gene, NANOG. Named after the Celtic legend of Tir NaNog (land of the ever young). When NANOG was forced to remain active, embryonic stem cells were able to grow in media deficient in factors usually required for self-renewal and did not lose their pluripotency even when treated with chemical agents that usually induce differentiation. Understanding the full capacity of NANOG to influence stem cell self-renewal and elucidation of the underlying molecular pathways regulated by this gene will provide valuable insights into the establishment and manipulation of stem cell lines from embryonic and adult tissues.Read moreRead less
The Role Of TAP And MHC Class I Expression In The Response To Melanoma Immunotherapy Using Autolgous Dendritic Cells
Funder
National Health and Medical Research Council
Funding Amount
$337,811.00
Summary
Treatment for patients with malignant melanoma whose disease has spread, or metastasised, to sites distant from the original melanoma is usually unsuccessful. At this stage of the disease there is no known curative treatment with conventional surgery, radiation or chemotherapy. Occasionally, however, melanoma in its early stages is successfully dealt with by the natural response of the immune system. In these cases, the immune system generates cancer-controlling killer T lymphocytes that enter t ....Treatment for patients with malignant melanoma whose disease has spread, or metastasised, to sites distant from the original melanoma is usually unsuccessful. At this stage of the disease there is no known curative treatment with conventional surgery, radiation or chemotherapy. Occasionally, however, melanoma in its early stages is successfully dealt with by the natural response of the immune system. In these cases, the immune system generates cancer-controlling killer T lymphocytes that enter the melanoma and kill the tumour cells. Killer T lymphocytes are generated by the lymph glands when the immune system is presented with melanoma cell components, or antigens, by specialised cells known as dendritic cells. This project consists of a clinical trial that aims to boost the natural ability of the immune system to generate killer cells by growing dendritic cells from the blood, mixing them with melanoma antigens, and then inject the mixture. When injected into the skin, dendritic cells quickly move to lymph glands to generate killer T lymphocytes. T lymphocytes can find their way to melanoma deposits all over the body. The reasons for response or non-response to the vaccination will particularly be assessed in this project.Read moreRead less
The Roles Of EZH2 And FOXO1A In CNS-PNET Pathogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$467,517.00
Summary
Although CNS-PNETs are the most common embryonal CNS tumours of childhood and cause significant mortality and morbidity, there is a very limited understanding of the pathogenesis of this aggressive disease. This situation is a major handicap to the development of more specific and effective therapies. While a better understanding of the fundamental pathology of CNS-PNETs will have immediate diagnostic implications, the elucidation of the biochemical pathways that are disrupted in these tumours w ....Although CNS-PNETs are the most common embryonal CNS tumours of childhood and cause significant mortality and morbidity, there is a very limited understanding of the pathogenesis of this aggressive disease. This situation is a major handicap to the development of more specific and effective therapies. While a better understanding of the fundamental pathology of CNS-PNETs will have immediate diagnostic implications, the elucidation of the biochemical pathways that are disrupted in these tumours will facilitate the design of new drugs that are specifically directed towards the critical proteins in these pathways. The identification of specific genes and-or pathways that are deregulated in CNS-PNET cells is essential for the development of safer, more directed, and more effective therapies that are urgently required for the treatment of those with this devastating disease.Read moreRead less
Development Of A Novel Therapy For The Treatment Of Epidermal Squamous Cell Carcinoma
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Squamous cell carcinomas (SCC) are the most common life-threatening form of skin cancer in Australia. SCCs commonly arise in areas of the body that have been exposed to excessive amounts of UV irradiation. The cells of the skin from which SCCs are derived are called keratinocytes. UV irradiation causes lesions within these cells such that their growth and maturation are disrupted leading to deregulated growth and maturation and hence tumour formation. We have previously identified a protein, E2F ....Squamous cell carcinomas (SCC) are the most common life-threatening form of skin cancer in Australia. SCCs commonly arise in areas of the body that have been exposed to excessive amounts of UV irradiation. The cells of the skin from which SCCs are derived are called keratinocytes. UV irradiation causes lesions within these cells such that their growth and maturation are disrupted leading to deregulated growth and maturation and hence tumour formation. We have previously identified a protein, E2F, that is central to this process and whose inhibition leads to decreased cancer cell growth. During the course of these studies we noted that the deregulation of E2F could also lead to the disruption of keratinocyte maturation. This led us to propose that the inhibition of E2F in SCCs may result in both decreased cancer cell growth as well as the reinstatement of a normal maturation process. this would make E2F inhibitors a very attractive therapeutic for treating SCC. In the present study we aim to explore the ability and the mechanism by which E2F modulates keratinocyte proliferation and maturation. This will be done in vitro as well as in animal models of SCC. These studies will be required in order to take the E2F inhibitors into clinical trials.Read moreRead less
Hormonal Control Of Serotli Cell Maturation And Function
Funder
National Health and Medical Research Council
Funding Amount
$512,898.00
Summary
This project will determine the key roles of androgen in the Sertoli cell, a unique highly specialised cell that provides essential nutritional and structural support for sperm production. Androgen acts via the androgen receptor (AR), which is vital for initiating and maintaining sperm development. In current NHMRC-funded research we successfully established new mouse models designed to study AR, in particular its regulation of gene expression, in the Sertoli cell. We revealed that genomic AR ac ....This project will determine the key roles of androgen in the Sertoli cell, a unique highly specialised cell that provides essential nutritional and structural support for sperm production. Androgen acts via the androgen receptor (AR), which is vital for initiating and maintaining sperm development. In current NHMRC-funded research we successfully established new mouse models designed to study AR, in particular its regulation of gene expression, in the Sertoli cell. We revealed that genomic AR activity within Sertoli cells is essential for 'induction' of complete sperm development. Ongoing work will develop unique 'inducible' transgenic models that will allow, for the first time, selective analysis of Sertoli AR in both 'developing' and 'adult' testes. Our innovative models will allow AR function to be switched on or off at any stage of development, providing unique opportunity to determine the key AR-regulated factors and pathways controlling induction, maintenance or restoration of sperm production. In past NHMRC research we created a novel transgenic model to study another major reproductive hormone, FSH. Using the hormone-deficient background of 'hpg' mice, we found that androgen and FSH act synergistically in the developing 'meiotic' germ cells that form sperm. Using the latest microarray gene technology we generated datasets of androgen-regulated genes with or without FSH activity, which combined with our unique transgenic AR and FSH models, will be used to identify key pathways, including those enhanced by androgen-FSH synergism, in the early testicular response. Our research will provide new knowledge of the precise roles and pathways of testicular AR actions, to ultimately identify key genetic and regulatory factors as targets for significantly improved therapy for male infertility, gonadal tumours, or contraception.Read moreRead less
The Sertoli Cell: Master Regulator Of Hormone-induced Spermatogenic Development
Funder
National Health and Medical Research Council
Funding Amount
$563,536.00
Summary
This project will determine the key roles of major hormones (testosterone, follicle-stimulating hormone, Vitamin A) in Sertoli cells, unique highly specialised cells found in the testis that provide essential nutritional and structural support for sperm production. This research will provide new understanding of the biological pathways controlling sperm development, leading to new molecular targets for infertility or cancer treatment or diagnosis, or new contraceptive strategies for men.
Influence Of TNF And TGF-beta On Langerhans Cell Mobilisation From Regressor And Progressor Skin Tumours
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Skin cancer is the most common type of cancer in humans. It is caused by the ultraviolet wavelengths found in sunlight. Australia has the highest incidence of skin cancer in the world, due to the large amount of sun exposure experienced by Australians during work and leisure. Considerable research needs to be directed towards this disease to understand how it forms and how it can be treated. Skin cancer can be controlled by the immune system, which in some cases is able to destroy the cancer, so ....Skin cancer is the most common type of cancer in humans. It is caused by the ultraviolet wavelengths found in sunlight. Australia has the highest incidence of skin cancer in the world, due to the large amount of sun exposure experienced by Australians during work and leisure. Considerable research needs to be directed towards this disease to understand how it forms and how it can be treated. Skin cancer can be controlled by the immune system, which in some cases is able to destroy the cancer, so that it disappears, or regresses. Other skin tumours fail to be destroyed by the immune system and therefore grow progressively. Differences between progressor and regressor tumours can help define why the immune system is able to destroy some but not other tumours. The cell of the immune system that is responsible for initiating immune responses against skin cancer is called the Langerhans cell. This cell migrates between the cancer and the local lymph node, where it activates lymphocytes to leave the lymph node and destroy the cancer. Our studies have shown that a major difference between progressor and regressor skin tumours is the ability of Langerhans cells to migrate from these tumours. Skin tumours produce cytokines (hormone like molecules) which enhance or inhibit Langerhans cell mobilization from the tumour. We have identified some of the cytokines involved, and plan to study how these cytokines interfere with this process and whether they do this by increasing the production of other factors, or by having a direct influence on the Langerhans cells. This knowledge would increase our ability to utilize these cells for treatment of cancer. This study will also further basic understanding of the biological factors which regulate the movement of this important cell from our tissues to the draining lymph node, which is of fundamental importance in the development of immunity.Read moreRead less