MECHANISMS OF ABNORMAL EXPRESSION OF THE IGF2 GENE IN DISORDERS AFFECTING FOETAL GROWTH
Funder
National Health and Medical Research Council
Funding Amount
$560,434.00
Summary
The IGF2 gene is crucial for foetal growth. Only the copy inherited from the father is active, a phenomenon named parental imprinting. In some children with foetal overgrowth or growth retardation, the deregulation of imprinting of the IGF2 gene during the first days of foetal development will influence subsequent growth and will also have major implications in post-natal and adult life. We will investigate the mechanisms resulting in abnormal imprinting of the IGF2 early in development.
Hypoglycaemia In Young Patients With Type 1 Diabetes: Pathophysiology, Predisposition And Preventive Strategies
Funder
National Health and Medical Research Council
Funding Amount
$2,680,000.00
Summary
The vision of this proposal is to bring together an active team of experienced investigators that will address important clinical problems affecting the management of children and adolescents with type 1 diabetes. Along with facilities and resources already under development, the program will further establish a core of investigators dedicated to patient centred and clinical research that will facilitate scientific advances to be put into practice. The incidence of type 1 diabetes is continuing ....The vision of this proposal is to bring together an active team of experienced investigators that will address important clinical problems affecting the management of children and adolescents with type 1 diabetes. Along with facilities and resources already under development, the program will further establish a core of investigators dedicated to patient centred and clinical research that will facilitate scientific advances to be put into practice. The incidence of type 1 diabetes is continuing to increase particularly in the young. As we enter the 21st century, insulin treatment aimed at restoring blood glucose levels as close to the normal as possible remains the most effective way to prevent the devastating long-term complications of the disease. Unfortunately this is difficult to achieve largely because insulin therapy is frequently associated with the development of low blood glucose or hypoglycaemia. Hyperglycaemia results in unpleasant symptoms if mild but if severe it can produce convulsions or unconsciousness. The fear of hypoglycaemia is ever present for the patient and their family, this not only significantly impairs quality of life but importantly also severely restricts attempts to control diabetes. One of the major goals of this research program will be to address important unanswered questions related to the development of hyperglycaemia in children and adolescents with diabetes. The research team will examine in detail the protective physiological mechanisms against hyperglycaemia that are deranged in diabetes, they will also study more closely those situations that are known to predispose to hyperglycaemia such as sleep and exercise as well as how the brain is affected as blood glucose falls. By taking this approach we hope to be able to devise management strategies that will lessen the impact of hyperglycaemia in diabetes treatment. It is anticipated that this in turn will contribute to the prevention of diabetes complications as well as reduce the burden of the disease for the patient and his or her family. A second goal of this research program will be to develop an internationally unique resource that will be available to all diabetes investigators. We will build on an already established population based database of all the children and adolescents with diabetes in Western Australia as well as complete a DNA bank of these patients and their families. Thus in addition to bringing together an effective team of researchers, this program will further develop resources that can be central to addressing other important questions related to the causes of diabetes and its complications.Read moreRead less
The Role Of Liver Fructose-1,6-phosphatase (FBPase) In Body Weight Regulation
Funder
National Health and Medical Research Council
Funding Amount
$494,718.00
Summary
We have shown that fructose-1,6-bisphosphatase (FBPase), an enzyme important in producing sugar from the liver and one that is connected to Type 2 diabetes, does not cause an increase in sugar production when there is more of the enzyme in mouse livers. It does, however, lower both body weight and the amount of food the mice consume. We therefore hypothesise that liver FBPase is important in controlling body weight in humans and our project aims to find out exactly how and why this happens.
Association Between Birthweight And The Metabolic Syndrome - A Study In Twins.
Funder
National Health and Medical Research Council
Funding Amount
$95,880.00
Summary
The Metabolic Syndrome is a shorthand term for a collection of disorders in the same individual; including Diabetes, high cholesterol levels, hypertension, atherosclerosis and obesity. These conditions have previously been assumed to occur because of genetic influences, acting in combination with the individual's lifestyle. However, another factor may also be important in causing the metabolic syndrome. A recent theory suggests that adverse events occurring during fetal development may result in ....The Metabolic Syndrome is a shorthand term for a collection of disorders in the same individual; including Diabetes, high cholesterol levels, hypertension, atherosclerosis and obesity. These conditions have previously been assumed to occur because of genetic influences, acting in combination with the individual's lifestyle. However, another factor may also be important in causing the metabolic syndrome. A recent theory suggests that adverse events occurring during fetal development may result in low birth weight and lead to metabolic changes which cause the metabolic syndrome in adulthood. This theory, if true, would have profound implications for the prevention of these common problems; which are the leading cause of death in developed countries. The validity of the Fetal Origins Hypothesis is curently uncertain. Confounding genetic and environmental factors make it difficult to separate the role of genetic, fetal and environmental influences. Studies of twins have the potential to sort out this important question. We will study the association between birthweight and the metabolic syndrome in sets of identical twins who have identical genes and similar environmental backgrounds. We will use a set of metabolic and hormone tests to define the characteristics of each twin. We will also employ a novel non-invasive method of measuring cell metabolism using magnetic resonance spectroscopy. If we find that the twin with lower birthweight usually has more adverse features of the metabolic syndrome, this will point to an important cause of cardiovascular disease. This study will provide very important insights into the influence of early life on subsequent health and may lead to a dramatic changes in our approach to the prevention of common diseases. Improving the health and well-being of pregnant mothers and their babies may turn out to be one of the most important public health issues that we can address.Read moreRead less
Novel Actions Of Leptin In Implantation And Placental Function
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
The establishment, growth and function of the placenta is of critical importance to the successful maintenance and completion of pregnancy. The placenta is effectively the lifeline of the growing fetus through its supply of nutrients, removal of wastes and coordination of hormone signals that regulate fetal growth and development. Among these signals the hormone leptin, which is produced primarily by fat cells and regulates food intake, has been identified as a crucial player in the control of f ....The establishment, growth and function of the placenta is of critical importance to the successful maintenance and completion of pregnancy. The placenta is effectively the lifeline of the growing fetus through its supply of nutrients, removal of wastes and coordination of hormone signals that regulate fetal growth and development. Among these signals the hormone leptin, which is produced primarily by fat cells and regulates food intake, has been identified as a crucial player in the control of fetal growth. In human pregnancy, the placenta becomes an additional major source of leptin, and this is secreted into the mother and the fetus. Recent work in animal models also indicates that the process of implantation, whereby the embryo embeds itself in the lining of the uterus and establishes a placenta, cannot proceed in the absence of leptin. But how leptin exerts these critical effects on the implantation process and placental function is not known. In this study we will explore several potential actions of leptin in the uterus and placenta, and examine whether the leptin signaling system is aberrant in cases where the fetus does not grow normally. Of particular interest is the possible interaction of leptin with another group of important signaling molecules called the peroxisome proliferator-activated receptors, or PPARs. One of these, PPAR-gamma, plays an indispensable role in the establishment of the placenta, particularly in relation to the formation of blood vessels, a process that is also a target for leptin action. Several lines of evidence, most notably in fat cells, suggest that both PPAR-gamma and leptin regulate common aspects of cell function. Such interactions provide us with important clues as to how leptin and the PPARs could work together to promote the optimal establishment, growth and function of the placenta, and these will be explored in this project.Read moreRead less
Interactions Between Fetal Programming And Postnatal Diet In Development Of The Metabolic Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$445,578.00
Summary
More than 50,000 Australians die annually from cardiovascular disease, accounting for almost 40% of all deaths. Obesity and high blood pressure are both key risk factors for cardiovascular disease, and so it is crucial that we understand the underlying causes of these conditions and how lifestyle changes, such as diet, can prevent them. We now know that several adult-onset diseases, including high blood pressure, obesity and diabetes, are influenced by how well we grow and develop as a fetus. Th ....More than 50,000 Australians die annually from cardiovascular disease, accounting for almost 40% of all deaths. Obesity and high blood pressure are both key risk factors for cardiovascular disease, and so it is crucial that we understand the underlying causes of these conditions and how lifestyle changes, such as diet, can prevent them. We now know that several adult-onset diseases, including high blood pressure, obesity and diabetes, are influenced by how well we grow and develop as a fetus. This effect, known as 'fetal programming', means that if we have a poor environment as a fetus (eg, maternal undernutrition), we are more likely to develop health problems such as high blood pressure many years later. In this study we are interested in how the events in fetal life 'program' these later health problems, and how we might reverse the adverse effects by lifestyle changes after birth. We have developed an animal model in which high blood pressure and problems with fat and muscle function that can lead to obesity and diabetes. These detrimental effects on adult health can be completely prevented in our model by placing offspring on a diet rich in omega-3 fats from the time of birth. These fats are commonly found in fish oil and are well known for their beneficial effects on cardiovascular function. The present proposal will extend these findings by determining whether omega-3 fatty acids can reverse the adverse programming outcomes after they have emerged in adult life. We will also investigate whether fetal programming effects are made even worse by the consumption of excess total dietary fat during development to adulthood, and if this effect can also be overcome by supplementation of the diet with omega-3 fats.Read moreRead less
Mechanisms Of Negative Feedback Regulation Of GnRH By Testosterone In Males
Funder
National Health and Medical Research Council
Funding Amount
$243,336.00
Summary
This project will improve our knowledge of the hormonal control of reproduction in males. The hormone testosterone, produced by the testes, acts on the brain to control the secretion of a substance called gonadotrophin releasing hormone (GnRH). GnRH acts on a small gland at the base of the brain to cause the production of hormones called gonadotrophins, that are essential for reproduction. These gonadotrophins act on the testes to ensure the production of sperm and other hormones, including test ....This project will improve our knowledge of the hormonal control of reproduction in males. The hormone testosterone, produced by the testes, acts on the brain to control the secretion of a substance called gonadotrophin releasing hormone (GnRH). GnRH acts on a small gland at the base of the brain to cause the production of hormones called gonadotrophins, that are essential for reproduction. These gonadotrophins act on the testes to ensure the production of sperm and other hormones, including testosterone. We plan to determine how testosterone acts on the brain to control GnRH secretion. To do this we will use male sheep and conduct a series of experiments designed to show where in the brain testosterone acts to ultimately affect the nerve cells that produce GnRH. Testosterone and similar compounds are increasingly being used as treatments for infertility, as a male contraception and misused as anabolic steroids. A thorough knowledge of how testosterone acts in the brain is necessary to improve treatments for reproductive disorders and ultimately to improve reproductive health in men.Read moreRead less
IGF BINDING PROTEIN-2 A MODULATOR OF IGF ACTION IN DEVELOPING AND NEOPLASTIC NEURONAL CELLS.
Funder
National Health and Medical Research Council
Funding Amount
$436,980.00
Summary
In early life the brain undergoes rapid growth and remodelling, a process regulated by many factors including the insulin-like growth factor (IGF) system, which potently enhances nerve cell (neuron) survival. Similarly, this system is active in response to brain injury such a stroke, but it may also enhance tumor survival. The regulation of availability of IGFs to the neuron is critical in all these processes. IGF binding protein-2 (IGFBP-2), which is highly abundant in the developing or damaged ....In early life the brain undergoes rapid growth and remodelling, a process regulated by many factors including the insulin-like growth factor (IGF) system, which potently enhances nerve cell (neuron) survival. Similarly, this system is active in response to brain injury such a stroke, but it may also enhance tumor survival. The regulation of availability of IGFs to the neuron is critical in all these processes. IGF binding protein-2 (IGFBP-2), which is highly abundant in the developing or damaged brain, and in tumours, plays a key role on the surface of neurons in regulating IGF availability. We have shown that IGFBP-2 associates with a specialised protein on the nerve cells, where it is further processed to smaller fragments. We believe that these processes are reactivated following brain injury or in cancer states where IGFBP-2 is highly abundant. We propose to determine how IGFBP-2 influences IGF action on the nerve cell surface, and to further ascertain the function of each step in this process. We will achieve this by examining the effects of the mutated version of IGFBP-2, designed to either prevent its binding to the cell surface or its processing to smaller fragments. We will use various human and mouse nerve cell for these studies, which will not only provide greater understanding of the regulation of IGF availability to developing brain cell, but also point to how these processes may be involved in enhancement of recovery from injury or stroke, or possibly in acceleration of tumour growth. The finding of this study will offer the potential for new and exciting treatment designed to alter the function of the IGF system, to either make it more active in response to brain injury or stroke, or less active in brain tumours.Read moreRead less
PRE CLINICAL TRIAL WITH FETAL PIG INSULIN-PRODUCING CELLS
Funder
National Health and Medical Research Council
Funding Amount
$292,416.00
Summary
If fetal pig cells are to be of value in normalizing blood glucose levels in diabetic people once transplanted, they must survive and mature after being grafted. The pre-clinical study proposed will examine several novel issues that are of direct relevance to future clinical trials. The diabetic pig will be used as recipient to address when the fetal cell matures after it is transplanted, how long the grafted cells will maintain normal blood glucose levels, and at which site it is most appropria ....If fetal pig cells are to be of value in normalizing blood glucose levels in diabetic people once transplanted, they must survive and mature after being grafted. The pre-clinical study proposed will examine several novel issues that are of direct relevance to future clinical trials. The diabetic pig will be used as recipient to address when the fetal cell matures after it is transplanted, how long the grafted cells will maintain normal blood glucose levels, and at which site it is most appropriate to transplant the cells. The baboon will be used as recipient to address the safety of transplanting the pig cells, especially from the pig endogenous retrovirus, and whether the immunosuppressive regime proposed for use in humans will prevent cellular rejection. The diabetic baboon will be used in the final experiment step to determine if normalization of blood glucose levels can be achieved in this xenografted animal just as it can in the diabetic pig.Read moreRead less