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.
Mechanisms Of Abnormal Expression Of The IGF2 Gene In Disorders Affectin Foetal Growth
Funder
National Health and Medical Research Council
Funding Amount
$420,872.00
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 IGF2 early in development.
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
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