Perinatal And Intergenerational Influences On Adult Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$438,520.00
Summary
The aim of this project is to determine the effects of restriction of nutrient supply before and after birth on growth and the development of adult onset diabetes. Being born small and its associated neonatal catch-up growth independently predict adult diabetes. Placental restriction is a major cause of reduced nutrition and growth before birth and is implicated in this programming of disease. Our novel findings suggest that placental compromise increases appetite but also impairs milk quality a ....The aim of this project is to determine the effects of restriction of nutrient supply before and after birth on growth and the development of adult onset diabetes. Being born small and its associated neonatal catch-up growth independently predict adult diabetes. Placental restriction is a major cause of reduced nutrition and growth before birth and is implicated in this programming of disease. Our novel findings suggest that placental compromise increases appetite but also impairs milk quality and supply which limits overfeeding and catch-up growth initially, but on weaning, may independently lead to diabetes. We will determine if this is a direct result of poor nutrition and made worse by overfeeding in response to restored nutrition. We hypothesize that placental compromise permanently reduces an individual's metabolic capacity and that the extent of availability of nutrition after birth determines the consequences for insulin action and increased body fat. Manipulations of postnatal nutrition (by cross-fostering) and fat oxidation will be performed, which are pivotal to understanding the roles of catch-up growth and increased food intake in disease onset. We have found that cross-fostering small rat pups at birth onto mothers with normal lactation improves growth during lactation. The proposed studies will establish the cross-fostering effect on the development of diabetes and identify a developmental stage during which nutritional or other manipulations may have beneficial consequences for the health of the breastfeeding small infant. We propose to determine whether adult females, exposed to placental restriction as a fetus, produce offspring that develop diabetes, and establish whether this effect is caused by programming before conception and-or an altered fetal environment. Identification of critical periods after birth, rather than before, would offer a greater likelihood that practical public health interventions can be developed to improve adult health.Read moreRead less
Pathophysiology And Prevention Of Methotrexate Chemotherapy-induced Bone Growth Defects
Funder
National Health and Medical Research Council
Funding Amount
$622,598.00
Summary
Childhood chemotherapy often causes growth arrest, osteoporosis, and fractures in cancer patients and survivors. Using a rat model, this project will study how the most commonly used chemotherapy drug methotrexate causes bone growth defects and examine any protective effects of two natural-derived substances. This work will increase our knowledge on chemotherapy-induced bone growth defects, and will be useful for developing a preventative treatment.
Early Predictors And Body Composition Changes Associated With Adiposity Rebound
Funder
National Health and Medical Research Council
Funding Amount
$201,650.00
Summary
Overweight and obesity rates are increasing in children, and overweight children have higher risk of adult obesity and therefore diseases including heart attack, stroke and diabetes. The preschool years may offer opportunities to divert children from the path to obesity, before poor physical activity and nutritional habits become firmly established. Adiposity rebound is the time in a child's life (usually around 5 to 6 years of age) when body mass index (BMI) begins to increase after a steady de ....Overweight and obesity rates are increasing in children, and overweight children have higher risk of adult obesity and therefore diseases including heart attack, stroke and diabetes. The preschool years may offer opportunities to divert children from the path to obesity, before poor physical activity and nutritional habits become firmly established. Adiposity rebound is the time in a child's life (usually around 5 to 6 years of age) when body mass index (BMI) begins to increase after a steady decline in BMI in the preschool years. Early adiposity rebound is associated with increased BMI in later life. We don't yet know whether the early adiposity rebound causes the higher BMI, or whether it is simply an early sign of an already-established pathway of behavioural and environmental risk. We need a much better understanding of predictors of early adiposity rebound and the changes that occur to determine if age at adiposity rebound is a modifiable risk factor for adult obesity. This study will document the process and timing of adiposity rebound and the changes in percent body fat and lean body mass that occur during that time. We will also determine whether risk and protective factors for early adiposity rebound and overweight at age 6 years are the same or different. We will study over 400 children on whom extensive data have been collected since birth, including period of gestation, birth weight and length. At various stages during their first two years of life, height, weight, feeding patterns and development were recorded. We will measure BMI and perform bioimpedance analysis (BIA) on these children six times between 4 and 6 years of age. BIA provides a measure of body fat and lean mass that is well accepted by children. This will help determine the relationship between changing BMI at different ages and the fat-to-lean mass ratios associated with those changes. This study is the first to consider body composition changes during adiposity rebound.Read moreRead less
Roles Of Injury-induced Inflammatory Response In Regulating Bony Repair At Injured Growth Plate Cartilage
Funder
National Health and Medical Research Council
Funding Amount
$366,301.00
Summary
Children's growth plate cartilage is responsible for bone lengthening. Due to popularity of sports and play, trauma-induced growth plate damage and subsequently bone growth defects are common in children, with up to 30% of growth plate injury cases resulting in growth abnormality, for which the present surgical correction is highly invasive and not fully effective. Although we know that the growth plate injury-induced bone growth defects result from bony repair of the injured growth cartilage, w ....Children's growth plate cartilage is responsible for bone lengthening. Due to popularity of sports and play, trauma-induced growth plate damage and subsequently bone growth defects are common in children, with up to 30% of growth plate injury cases resulting in growth abnormality, for which the present surgical correction is highly invasive and not fully effective. Although we know that the growth plate injury-induced bone growth defects result from bony repair of the injured growth cartilage, we largely don't understand why and how this bony repair occurs. Understanding mechanisms for this faulty bony repair of injured growth plate will be critical prior to effective biological treatments can be developed. Recently, using an injury model in young rats, we found that bony tissue formation at injured growth plate is preceded sequentially by inflammatory, fibrogenic, chondrogenic and osteogenic responses. The inflammatory response is an initial event and our recent studies suggest that inflammatory response recruits inflammatory cells and produces important molecules that could significantly influence subsequent fibrogenic, chondrogenic and osteogenic events leading to the bony repair of the injured growth plate cartilage. The current proposal further addresses roles of the inflammatory response and the molecular pathways of this response in regulating downstream bony repair events. This project will generate novel understanding on the faulty bony repair of injured growth plate, and will provide valuable information for developing cost-effective and simple therapeutic intervention that aims to prevent bony repair and to enhance cartilage regeneration of the injured growth plate in children.Read moreRead less
Role Of The Nuclear Growth Hormone Receptor In Cell Proliferation And Function
Funder
National Health and Medical Research Council
Funding Amount
$477,750.00
Summary
In addition to final height, growth hormone regulates many tissues in the body, and through these, regulates metabolism, body composition, vitality and aspects of ageing. However, there is some evidence that GH can also promote cancer, notably colon and blood cell cancers. Our discovery of the receptor for growth hormone in the cell nucleus, notably in many cancers, has led us to investigate the role of the nuclear GH receptor. We have found that targeting this receptor to the nucleus allows the ....In addition to final height, growth hormone regulates many tissues in the body, and through these, regulates metabolism, body composition, vitality and aspects of ageing. However, there is some evidence that GH can also promote cancer, notably colon and blood cell cancers. Our discovery of the receptor for growth hormone in the cell nucleus, notably in many cancers, has led us to investigate the role of the nuclear GH receptor. We have found that targeting this receptor to the nucleus allows the cell to divide without the need for the normal factors which initiate cell division and survival. We have also found that a part of the GH receptor acts as a gene activator, and have identified some of the nuclear proteins which bind to the receptor and make this so. This proposal aims to establish the link between the nuclear GH receptor and cell division, both mechanistically, and in live animals. We also plan to establish if nuclear localizing the receptor artificially results in cancer formation. The outcome would provide an index of risk from current GH therapy, and could lead to a new cancer therapy.Read moreRead less
Early School-Age Outcomes After Exposure To Repeat Prenatal Corticosteroids - A Randomised Controlled Trial
Funder
National Health and Medical Research Council
Funding Amount
$1,083,964.00
Summary
AIMS OF THE RESEARCH We have recently concluded a large clinical trial in Australia and New Zealand of repeat dose of antenatal corticosteroids given to women who were likely to deliver their baby too early (before 34 weeks of pregnancy). We have been able to show that repeat doses of corticosteroids before birth significantly reduces the risk of the baby developing respiratory difficulties after birth from 41.4% to 32.8%. However, we are not sure if this potentially important improvement will t ....AIMS OF THE RESEARCH We have recently concluded a large clinical trial in Australia and New Zealand of repeat dose of antenatal corticosteroids given to women who were likely to deliver their baby too early (before 34 weeks of pregnancy). We have been able to show that repeat doses of corticosteroids before birth significantly reduces the risk of the baby developing respiratory difficulties after birth from 41.4% to 32.8%. However, we are not sure if this potentially important improvement will translate into better outcomes for the children as they grow older and reach school-age. As there are many examples of treatments given around the time of birth that have been shown to have some short-term benefits, but substantial long-term harms, we must be as certain as we can be that any advance in one small area of health is not counterbalanced by disadvantages in other health areas. This is particularly important to find out for repeat antenatal corticosteroids given the earlier conflicting reports from non-randomised studies. We plan to assess the 1085 survivors from our earlier clinical trial of repeat dose of prenatal corticosteroids when they are of early school age. We will assess their movement and other important areas of their brain function, as well as their school progress, blood pressure, lung function and general health and growth. EXPECTED OUTCOMES OF THE RESEARCH If we find important improvements in health outcomes at school-age in children exposed to repeat corticosteroids, without any substantial couterbalancing adverse effects, repeat steroids will be recommended standard therapy in women who are likely to give birth to their baby very early. This will lead to a reduction in the burden of ill health.Read moreRead less
Repeated Prenatal Corticosteroids: Effects On Childhood Development, Behaviour, Growth And Health
Funder
National Health and Medical Research Council
Funding Amount
$265,900.00
Summary
Infants born preterm are at high risk of needing help with their breathing to survive. Corticosteroids given to the mother prior to preterm birth can substantially reduce these risks, although the beneficial effects of these drugs only seem to last seven days. Because of this there has been a tendancy to repeat the dose of prenatal steroids after seven days in women who remain at continued risk of very preterm birth. There has been no formal assessment of whether or not repeating the dose of pre ....Infants born preterm are at high risk of needing help with their breathing to survive. Corticosteroids given to the mother prior to preterm birth can substantially reduce these risks, although the beneficial effects of these drugs only seem to last seven days. Because of this there has been a tendancy to repeat the dose of prenatal steroids after seven days in women who remain at continued risk of very preterm birth. There has been no formal assessment of whether or not repeating the dose of prenatal corticosteroids is beneficial or harmful. In this clinical trial we will test what effect, if any, repeat doses of corticosteroids given to women who remain at risk of preterm birth, have on children at the age of two years Women are eligible for the trial if at of less than 32 weeks of pregnancy, they have received corticosteroids seven or more days ago, and they are considered to be at continued risk of preterm birth. Women are randomised to one of the two treatment groups. Half the women will receive a weekly intramuscular injection of corticosteroids up to the time of birth or 32 weeks gestation, whichever is earlier, whilst the risk of very preterm birth remains. The other half of the women will receive a saline placebo injection. Chance will decide which treatment the women receives. In this study all children who survive to 2 years corrected age will be assessed to see if they have any problems with their health, growth and development. In particular we will assess how well they can walk, talk, understand, see and hear. The trial will be able to assess whether repeat doses of prenatal corticosteroids are helpful or not for infants at risk of being born very preterm by comparing the short term effects on infant health after birth and whilst in hospital with the effects on the child's later health, growth and development. An economic assessment of repeat doses of prenatal corticosteroids will be made in these children.Read moreRead less
“I am a biomedical scientist undertaking basic and clinical research on the pathophysiology of growth plate injury and repair, which critically impacts on children’s bone growth and growth disorders. I aim to investigate the underlying mechanisms and deve
Prenatal Placental And Postnatal Mammary Programming Of Cardiovascular And Renal Diseases
Funder
National Health and Medical Research Council
Funding Amount
$503,776.00
Summary
Being born small and the associated catch-up growth, independently predict adult hypertension. Reduced placental blood flow is a major cause of fetal growth restriction and is implicated in programming adult disease. We are the first to demonstrate that placental compromise in rats also adversely affects breast development, milk quality and supply, which further impair growth during lactation. This is followed by accelerated growth after weaning, programming more adverse outcomes. Using a rat mo ....Being born small and the associated catch-up growth, independently predict adult hypertension. Reduced placental blood flow is a major cause of fetal growth restriction and is implicated in programming adult disease. We are the first to demonstrate that placental compromise in rats also adversely affects breast development, milk quality and supply, which further impair growth during lactation. This is followed by accelerated growth after weaning, programming more adverse outcomes. Using a rat model, we will determine for the first time if restricted nutrition before birth via the placenta or after birth via lactation increases the risk of developing high blood pressue and kidney and blood vessel dysfunction. Manipulations of nutrition after birth will be achieved by cross-fostering studies. We will establish whether a reduction in the number of functioning units (nephrons) in the kidney, alterations in key genes involved in kidney development and changes in blood vessel reactivity are associated with developing hypertension. We will manipulate the renin-angiotensin system (RAS), which is important in determining kidney function, to define its role in hypertension in this model. We propose that a common lifestyle insult, such as modest elevation in dietary salt, will evoke exaggerated responses in adult offspring who were born small. These studies will identify the mechanisms by which the kidney, vasculature and RAS contribute to the programming of hypertension and the relative roles of the prenatal and postnatal environments. Defining the underlying mechanisms responsible will provide insight into early life interventions that may lessen these adverse consequences for longer-term health. Identification of critical periods after birth, rather than before, would offer a greater likelihood that practical public health interventions can be developed to improve adult health in this emerging field.Read moreRead less
Early Origins, Progression And Aetiology Of Obesity, Metabolic Syndrome And Diabetes: A 30 Years Follow-up Study
Funder
National Health and Medical Research Council
Funding Amount
$1,194,979.00
Summary
This research proposal aims to use the unique existing Mater University Study of Pregnancy (MUSP) and its offspring data and conduct a 30-year follow-up of MUSP children to investigate the early origins, progression and causal pathways of obesity, metabolic syndrome and diabetes for young Australian. Findings of this study will extend our understanding of the factors driving these health problems with the ultimate aim of being able to reverse the obesity epidemic and improve public health.