Hypothalamic Signalling In Cortical And Trabecular Bone Anabolic Activity
Funder
National Health and Medical Research Council
Funding Amount
$472,770.00
Summary
Osteoporosis is a disease associated with an exponential rise in the number of fractures in the elderly. These fractures are so common that around 1 in 3 women and 1in four men will be affected. They cause pain, disability that can be permanent disability and are associated with premature death. Current treatments are able to effectively increase bone strength in osteoporotic patients but can not return bone strength to normal. Some new treatments can restore bone strength to some extent but the ....Osteoporosis is a disease associated with an exponential rise in the number of fractures in the elderly. These fractures are so common that around 1 in 3 women and 1in four men will be affected. They cause pain, disability that can be permanent disability and are associated with premature death. Current treatments are able to effectively increase bone strength in osteoporotic patients but can not return bone strength to normal. Some new treatments can restore bone strength to some extent but these are limited by expense and safety concerns. We have discovered a pathway in the brain that reduces bone formation and by blocking this pathway we can achieve doubling of the amount of bone in key bone sites. This occurs due to a marked increase in the amount of new bone formed. In fact, genetic manipulation of this pathway was able to double the speed at which bone is made by the skeleton. Excitingly, these increases in bone were possible in adult mice, suggesting such changes could be potential therapy for human patients. However, in order to be able to harness this pathway we must understand what molecules within the brain are responsible for the signals that reach the bone. Our proposal aims to identify the nerve signalling molecule(s) and the receptor for these signals within the brain that initiates the increase in bone formation. This project ultimately aims to identify a target for new therapies that could cause this beneficial effect by administration of a simple treatment, preferably by mouth in adult humans.Read moreRead less
Correction Of Diabetes In An Autoimmune Model Using Insulin-secreting Liver Cells.
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
Type I diabetes mellitus is caused by the autoimmune destruction of the beta cells of the pancreas that secrete insulin. The problems of the chronic complications of diabetes and the lack of donor tissue for transplantation, could theoretically be overcome by engineering from the patient's own cells, an artificial beta cell, i. e. a non-islet cell capable of synthesising, storing and secreting mature insulin in response to metabolic stimuli, such as glucose. The ultimate goal of this technology ....Type I diabetes mellitus is caused by the autoimmune destruction of the beta cells of the pancreas that secrete insulin. The problems of the chronic complications of diabetes and the lack of donor tissue for transplantation, could theoretically be overcome by engineering from the patient's own cells, an artificial beta cell, i. e. a non-islet cell capable of synthesising, storing and secreting mature insulin in response to metabolic stimuli, such as glucose. The ultimate goal of this technology is to deliver the insulin gene directly to a patient's own liver cells which would regulate insulin secretion in response to glucose and other substances that stimulate insulin secretion, controlling blood glucose without the need for immunosuppression. To accomplish this it must be possible to deliver the insulin gene efficiently to primary liver cells (cells derived from an animal's or human's body). Results from our laboratory using a non-pathogenic viral delivery system indicate that we can reverse diabetes in chemically induced diabetic rats by expression of insulin and a beta cell transcription factor NeuroD. The aim of this study is to repeat this in an auto-immune model of diabetes the nonobese diabetic mouse, which mimicks very closely the development of diabetes in humans. We will determine if we can reverse diabetes in these animals and determine if their response to glucose is normal over an extended period of time, with no attack by the factors of the immune system that stimulate the development of diabetes in man. The results from this research proposal should result in the delivery of the insulin gene to large numbers of primary liver cells that will then synthesise, store and secrete insulin in response to glucose. These cells would control blood glucose levels in patients without the need for immunosuppression.Read moreRead less
Androgen Receptor Signalling In Development And Progression Of Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$753,420.00
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 growth and survival, surgical or medical castration results in an initial tumour regression. However, tumours inevitably develop resistance to androgen ablation therapy and regrow. In this study we aim to provide the most comprehensive analysis to date of the role of androgen signalling in the initiation and progression of prostate cancer. This will enable us to identify the most effective means of eliminating androgen-dependent prostate tumours and identify tumours with high metastatic potential. Our studies will indicate whether treatments targeting androgen signalling are a more effective strategy to inhibit prostate cancer growth while minimising undesirable side effects.Read moreRead less
The Role Of The Novel Gene Herpud1 In Insulin Secretion In Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$502,370.00
Summary
A reduced ability to secrete insulin is the cause of high blood sugar in type 2 diabetes. This study has identified a gene called Herpud1 that affects insulin secretion. By studying the effects of this gene we are improving our knowledge of the defects that occur in Type 2 diabetes. This has the potential of providing better therapeutic strategies and identifying targets for the developments of better drug development.
Identification And Characterisation Of A Gene Causing Insulin Hypersecretion In A Mouse Model Of Diabetes Susceptibility
Funder
National Health and Medical Research Council
Funding Amount
$430,320.00
Summary
Diabetes is a disorder primarily characterised by the inability to produce and secrete the pancreatic hormone insulin, which regulates plasma sugar levels. This results in increased sugar levels which cause diabetic complications such as retinopathy and nephropathy. The inability to produce and secrete insulin is due to both defects in function as well as a reduction in pancreatic beta cells. Paradoxically it has been shown that some patients who are at risk of develping diabetes actually secret ....Diabetes is a disorder primarily characterised by the inability to produce and secrete the pancreatic hormone insulin, which regulates plasma sugar levels. This results in increased sugar levels which cause diabetic complications such as retinopathy and nephropathy. The inability to produce and secrete insulin is due to both defects in function as well as a reduction in pancreatic beta cells. Paradoxically it has been shown that some patients who are at risk of develping diabetes actually secrete more insulin than normal. Furthermore it has been suggested that this increase in insulin secretion actually may be associated with the decreased production and secretion of insulin characteristic of diabetes. The DBA-2 mouse is a model of reduced insulin production and secretion when exposed to high sugar levels or diabetes. However we have shown that in the normal non-stressed state DBA-2 mice actually secrete more insulin than normal and that this occurs from a very early age, suggesting that this trait is inherited. We have subsequently performed genetic studies and have identified a segment of DNA containing 10 genes associated with increased insulin secretion in DBA-2 mice. The level of one of these genes we have called Hip1 is increased 5-fold in DBA-2 mice, providing a candidate gene for increased insulin secretion in this model of diabetes susceptibility. However, whether Hip1 is also responsible for reduced insulin production and secretion in the DBA-2 mouse is not known. Therefore the overall hypothesis of this project is that the gene Hip1 which is associated with increased insulin secretion is also responsible for reduced insulin production and secretion when DBA-2 mice are exposed to high sugar or obesity. Determining why Hip1 is increased and whether it results in diabetes in DBA-2 mice may provide a reasonable candidate for the development of therapeutic interventions which may prevent the progression of diabetes in some patients.Read moreRead less
Unravelling The Mechanisms By Which Insulin Hypersecretion Is Detrimental To ß-cell Function And Survival In Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$727,758.00
Summary
Type 2 diabetes is associated with reduced levels of the hormone insulin that results in an increase in blood sugar. Evidence suggests that when the cells that make insulin are overworked they fail to produce the right amount of this hormone to keep blood sugar levels normal. In this proposal we will determine how overworking the insulin producing cells damages them and assess whether reducing the need to overwork is beneficial and thus lead to reduced blood sugar levels in Type 2 diabetes.
Type 2 diabetes represents an escalating global health problem. In Australia 7.2% of the population has diabetes but an additional 16% have difficulty handling glucose, a problem which frequently precedes the development of diabetes. Resistance of tissues to the action of insulin is an essential pre-requisite for type 2 diabetes but is also closely associated with the syndrome of obesity, dyslipidaemia, hypertension and cardiovascular diseases (Syndrome X). Genetic factors combined with a high c ....Type 2 diabetes represents an escalating global health problem. In Australia 7.2% of the population has diabetes but an additional 16% have difficulty handling glucose, a problem which frequently precedes the development of diabetes. Resistance of tissues to the action of insulin is an essential pre-requisite for type 2 diabetes but is also closely associated with the syndrome of obesity, dyslipidaemia, hypertension and cardiovascular diseases (Syndrome X). Genetic factors combined with a high caloric intake and a sedentary lifestyle are together responsible for the development of insulin resistance. From evidence that we and others have obtained in recent years it is evident that an important mediator of insulin resistance is the amount of fat which accumulates in muscle and liver. One way in which this abnormality seems to cause insulin resistance is through interference with the normal signalling mechanism which causes increased glucose metabolism in response to insulin. While experiments in cell systems have identified some candidate molecules that may be involved, a need exists to demonstrate whether their dysregulation actually causes the insulin resistance in the whole animal or human, or are merely associated with it. We will use novel techniques to manipulate the levels of one of these candidate genes, protein kinase B-Akt, and its regulators in the muscle of rodents. We will then examine the effects of these manipulations on insulin resistance using a combination of metabolic and molecular tests. Building upon earlier work we will also determine how important different subtypes of this molecule are for both normal and abnormal insulin-glucose metabolism, and whether these molecules or others in the pathway are more important in insulin resistance. This knowledge will be invaluable in tailoring specific novel treatment strategies or drugs for prevention or treatment of insulin resistance, and thus reducing the burden of type 2 diabetes and Syndrome X.Read moreRead less
Exploring Models For Antibody Mediated Endocrine Disease
Funder
National Health and Medical Research Council
Funding Amount
$140,949.00
Summary
Common endocrine disorders like Graves’ disease, are mediated by auto-antibodies, causing uncontrolled hormonal expression and undesirable effects. However, due to the limited understanding of the antibody interactions, the treatment is still focused on controlling the hormone production/interactions instead of targeting the underlying autoimmune processes. This project aims to further characterise the role the antibody through animal studies and developing novel treatments based on the research ....Common endocrine disorders like Graves’ disease, are mediated by auto-antibodies, causing uncontrolled hormonal expression and undesirable effects. However, due to the limited understanding of the antibody interactions, the treatment is still focused on controlling the hormone production/interactions instead of targeting the underlying autoimmune processes. This project aims to further characterise the role the antibody through animal studies and developing novel treatments based on the research.Read moreRead less