The Role Of Vitamin D In Beta Cell Function, Glucose Tolerance And Diabetes Mellitus.
Funder
National Health and Medical Research Council
Funding Amount
$102,820.00
Summary
A significant proportion of Australians are deficient in Vitamin D, a vitamin obtained from sunlight exposure and to a lesser extent from food. Vitamin D deficiency has been associated with increased risk of Type 2 diabetes. This study aims to demonstrate the mechanisms through which vitamin D affects the insulin-producing cells of the pancreas and to determine whether deficiency affects the body's handling of glucose and subsequent risk of Type 2 diabetes and diabetes in pregnancy.
Modulation Of Cytoskeletal Structure By Progesterone Receptor Isoforms
Funder
National Health and Medical Research Council
Funding Amount
$337,650.00
Summary
Ovarian hormones are fundamental regulators of normal cell growth and differentiation, and crucial to the development and progression of breast cancer. We have recently shown that the ovarian hormone progesterone can influence the expression of proteins in the cell scaffolding, known as the cytoskeleton. The cytoskeleton is responsible for maintaining cell shape, and there is growing evidence that alterations in the cytoskeleton can actually cause normal cells to become cancerous. We have shown ....Ovarian hormones are fundamental regulators of normal cell growth and differentiation, and crucial to the development and progression of breast cancer. We have recently shown that the ovarian hormone progesterone can influence the expression of proteins in the cell scaffolding, known as the cytoskeleton. The cytoskeleton is responsible for maintaining cell shape, and there is growing evidence that alterations in the cytoskeleton can actually cause normal cells to become cancerous. We have shown that progesterone affects the levels of a cytoskeletal protein called tropomyosin, which plays a pivotal role in cell shape maintenance. We have hypothesised that this effect may be important in the cell shape changes in breast cancer that lead to metastasis. In this grant, we will investigate the role of the progesterone receptor in controlling the expression of the cytokeleton; we will investigate whether cell shape changes caused by progesterone cause more aggressive behaviour in breast cancer cells and we will determine whether there are changes in cytokeletal proteins in breast tumours. This will provide a rational basis for further studies aimed at delineating the significance of hormonal regulation of cell architecture.Read moreRead less
Hormonal Influences In The Pathogenesis Of Ovarian Tumours
Funder
National Health and Medical Research Council
Funding Amount
$264,601.00
Summary
Ovarian cancer is one of the most common malignancies affecting the female reproductive system. We have found that two types of tumour of the ovary produce a hormone called inhibin; these tumours are also known to produce the steroid hormone estrogen. In these studies we are seeking to determine the genetic changes in the tumours that cause the production of these hormones. We suspect that these genetic changes are also the same changes which contribute to the development of the cancers. In orde ....Ovarian cancer is one of the most common malignancies affecting the female reproductive system. We have found that two types of tumour of the ovary produce a hormone called inhibin; these tumours are also known to produce the steroid hormone estrogen. In these studies we are seeking to determine the genetic changes in the tumours that cause the production of these hormones. We suspect that these genetic changes are also the same changes which contribute to the development of the cancers. In order to identify these genes we will draw on our knowledge of the genes that are important in the controlof growth and hormone secretion in normal ovarian cells. To assist this molecular analysis we will use two ovarian cell lines in culture that have many of the features of the primary tumours including inhibin secretion. We will also use new techniques to scan over 500 genes involved in tumours in general to see whether we detect any unusual or distinctive patterns in this sub-group of tumours. A genome wide scanning technique will be used to seek changes in the DNA of the tumours, inparticular loss of genetic material or amplification of regions. Identification of the genetic changes within these tumours should enable better systems of classification, enhance prognostication and provide specific targets for the development of appropriate treatment strategies.Read moreRead less
The Identification Of A Novel NIDDM Susceptibility Gene Localised To Human Chromosome 12q
Funder
National Health and Medical Research Council
Funding Amount
$438,055.00
Summary
Non-insulin dependent diabetes mellitus (adult-onset diabetes) is very common in Australia and is a major public health problem. It is a leading cause of kidney failure, blindness, heart attacks, strokes and amputations. Over 3% of the Australian population have adult-onset diabetes, and very few Australians have not been touched in some way by the shadow of diabetes. The precise cause of diabetes is unknown, however we do know that it tends to run in families, indicating that an inherited tende ....Non-insulin dependent diabetes mellitus (adult-onset diabetes) is very common in Australia and is a major public health problem. It is a leading cause of kidney failure, blindness, heart attacks, strokes and amputations. Over 3% of the Australian population have adult-onset diabetes, and very few Australians have not been touched in some way by the shadow of diabetes. The precise cause of diabetes is unknown, however we do know that it tends to run in families, indicating that an inherited tendency is important. By finding genes which cause diabetes we have the opportunity to unravel much of the mystery of this condition. This research program will find genes which cause diabetes by searching for them in large pedigrees in which many family members are affected by diabetes. Finding the genes which cause diabetes will have a significant impact in at least three major ways. Firstly, it will increase our understanding of the disease process. Secondly, it will be possible to develop tests to identify people at risk of diabetes at a very early stage so that therapy can be introduced and complications averted. Thirdly, it will be possible to develop new and more effective approaches for the prevention and treatment of diabetes.Read moreRead less
In this study, mouse models of disease will be used to determine the mechanisms by which the proinflammatory molecule called MIFpromotes the development of insulin resisitance and type 2 diabetes. We will also test whether therapeutic blockade of MIF can prevent the progression of disease in mice with established type 2 diabetes. Studies on tissue samples obtained from human patients will be used to confirm the human relevance of these findings.
Regulation And Functional Roles Of ADAM 10 Protease In Prostate Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
Prostate cancer is the second most common cause of cancer death among western males. Most deaths from prostate cancer are due to the development of secondary tumours (metastases) in other body organs. Metastasis involves actions of enzymes, (called metalloproteinases) which can break down the tissue structure surrounding tumour cells, and actions of a family of proteins (called integrins)that control how cells stick to each other or to other tissue components. Both these actions allow tumour cel ....Prostate cancer is the second most common cause of cancer death among western males. Most deaths from prostate cancer are due to the development of secondary tumours (metastases) in other body organs. Metastasis involves actions of enzymes, (called metalloproteinases) which can break down the tissue structure surrounding tumour cells, and actions of a family of proteins (called integrins)that control how cells stick to each other or to other tissue components. Both these actions allow tumour cells to break free from their original tissue positions, walk through surrounding tissue and deposit themselves at distant sites to form a secondary tumour. In this research we are looking at a protein, called ADAM-10, which belongs to a family of proteases, the ADAMs, which contain both A Disintegrin And Metalloprotease activity, hence their name. Our data suggest ADAM-10 is produced in large quantities by prostate cancer cells but can be differently located within these cells it sits on the outer membrane of normal or benign prostate glands but re-locates to the cell nucleus in high grade prostate cancer cells. We have also identified ADAM-10 protein in small membrane fragments that are commonly shed from prostate cancer cells. Preliminary evidence suggests that levels of ADAM-10 in each of these locations is regulated by growth factors and-or the male sex hormone, androgen, key hormones involved in prostate cancer growth and progression. We do not yet know what actions ADAM-10 has when it occurs in these different locations but believe the membrane form will be involved in metastasis, with the nuclear form being involved in regulating events within the nucleus, the control centre for the cell. This grant application aims to build on our novel observations and investigate the underlying mechanisms of ADAM-10 hormonal regulation and function. If proven, these issues may be important for the development, progression and future treatment of prostate cancer.Read moreRead less
Progesterone Regulation Of Epithelial Cell Lineages In The Breast
Funder
National Health and Medical Research Council
Funding Amount
$534,186.00
Summary
The ovaries play a pivotal role in breast cancer in ways that are unknown. Progesterone increases breast cancer risk, and response to hormonal treatments is critically associated with tumour progesterone receptor content, but how it does this is unknown. We will pursue our findings that progesterone influences cell types in the breast similar to those that become cancerous. This will uncover critical vulnerabilities in breast cancer development and potential targets for prevention and treatment.
Kallikrein Proteases Have Key Functional Roles In Peritoneal Invasion And Chemoresistance In Epithelial Ovarian Cancer
Funder
National Health and Medical Research Council
Funding Amount
$815,541.00
Summary
Only 30% of ovarian cancer patients with advanced disease survive for 5 years. This is because the cancer quickly spreads into the abdominal cavity and often becomes resistant to chemotherapy. We aim to use a new 3D culture system, mouse models and novel inhibitors to study the roles of 4 kallikrein enzymes in these events. The outcomes from this study will lead to a better understanding of the role of kallikreins in ovarian cancer and may lead to new treatment approaches.
The Role Of Ghrelin And Growth Hormone Releasing Hormone In The Autocrine Regulation Of Prostate Cancer Cell Growth
Funder
National Health and Medical Research Council
Funding Amount
$240,990.00
Summary
Insulin-like growth factor-I (IGF-I) is an important growth factor with a major role in the growth and development of many normal and tumour cells. Its production is controlled by growth hormone (GH), released from the pituitary gland at the base of the brain. GH releasing hormone (GHRH), a hormone released from higher centres in the brain, regulates the production of GH itself and now it is recognised that a second pathway, the ghrelin-GH secretagogue receptor (GHS-R) axis is also important in ....Insulin-like growth factor-I (IGF-I) is an important growth factor with a major role in the growth and development of many normal and tumour cells. Its production is controlled by growth hormone (GH), released from the pituitary gland at the base of the brain. GH releasing hormone (GHRH), a hormone released from higher centres in the brain, regulates the production of GH itself and now it is recognised that a second pathway, the ghrelin-GH secretagogue receptor (GHS-R) axis is also important in regulating GH release. There is growing evidence that the GHRH-GH-IGF axis has a significant role in prostate cancer, but little is known about how this happens. We also have evidence that the ghrelin-GHS-R axis is involved in prostate cancer, as prostate cancer cell lines produce both ghrelin and the receptor through which it acts. Our preliminary studies show that ghrelin enhances cell growth in these cells. GHRH blocking agents (antagonists) are potential treatments for prostate cancer, as they slow the growth of prostate tumours. How they act is unclear, but they might interfere with a locally active GHRH pathway in the prostate. This study aims to explore the role of ghrelin and GHRH in prostate cancer. Since there is an increase in the use of GHRH, GH and-or IGF-I and potentially ghrelin for the treatment of a variety of medical conditions, including some in the aging male, the need for a fuller understanding of the role of this axis in prostate cancer is increasingly important. Such information will lead to a deeper understanding of the actions of ghrelin and GHRH and provide potential opportunities for design of new therapies for prostate and other GH-IGF-responsive tumours.Read moreRead less
Androgen Receptor Signalling And Progression Of Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$462,750.00
Summary
Prostate cancer is a major health problem in Australia, being the second leading cause of cancer deaths in men. Although there have been improvements in the diagnosis and treatment of prostate cancer, there are no effective treatments for advanced (metastatic) disease that has spread to other parts of the body. Currently, the only therapy for advanced disease involves the reduction in circulating androgens such as testosterone by surgical or medical castration, i.e. androgen ablation. Because pr ....Prostate cancer is a major health problem in Australia, being the second leading cause of cancer deaths in men. Although there have been improvements in the diagnosis and treatment of prostate cancer, there are no effective treatments for advanced (metastatic) disease that has spread to other parts of the body. Currently, the only therapy for advanced disease involves the reduction in circulating androgens such as testosterone by surgical or medical castration, i.e. androgen ablation. Because prostate cells are dependent on testicular androgens for their survival, surgical or medical castration results in an initial tumour regression. However, tumours inevitably develop resistance to current forms of androgen ablation therapy. Inappropriate activation of androgen signalling by non-testicular androgens or other agents may stimulate tumour growth following androgen ablation. In this study, we aim to identify and characterise determinants of the specificity and sensitivity of activation of the androgen receptor, which is the primary mediator of androgen action. Current androgen ablation treatments for prostate cancer only target the availability of androgenic ligands. We propose that it is also necessary to target the androgen receptor itself, because it can be activated by ligands other than testicular androgens. Therefore, we will also evaluate a panel ofagents that target different aspects of the androgen signalling axis, combined with androgen ablation using a cyclical approach to prevent or delay disease progression.Read moreRead less