Does Caffeine Affect The Development Of The Very Immature Brain: Dose Response Relationship?
Funder
National Health and Medical Research Council
Funding Amount
$668,386.00
Summary
Premature birth is a major health problem worldwide. Preterm babies often develop apnoea of prematurity (AOP), which is commonly treated with caffeine. Trials indicate that preterm babies treated with low dose caffeine have less neurodevelopmental disabilities at 18 months. Higher doses of caffeine are often needed to reduce AOP but the risk of this is unknown. We will study the short and long-term effects of increasing doses of caffeine on the developing brain in a long-gestation species.
Neurosteroid Mediated Protection After Birth: Approaches For Maximising Protective Steroid Levels In The Neonatal Brain
Funder
National Health and Medical Research Council
Funding Amount
$450,703.00
Summary
Complications during pregnancy, birth asphyxia or premature birth can lead to neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neurosteroids are a group of steroids that regulate brain activity. These steroids protect brain cells from damage caused by an inadequate supply of oxygen by suppressing toxicity caused by excessive activity. We have shown that the levels of these protective steroids are remarkably high in the ....Complications during pregnancy, birth asphyxia or premature birth can lead to neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neurosteroids are a group of steroids that regulate brain activity. These steroids protect brain cells from damage caused by an inadequate supply of oxygen by suppressing toxicity caused by excessive activity. We have shown that the levels of these protective steroids are remarkably high in the fetal brain and levels rise further in response to fetal stress. The placenta contributes steroid precursors that help maintain these high neurosteroid levels. This placenta-fetal brain interaction comprises an internal mechanism that protects the fetal brain from adverse events during pregnancy. At birth, however, there is a dramatic decline in neurosteroid concentrations in the brain after the loss of the placental precursor supply. The fall in concentrations is even greater in animals that are born growth restricted. This suggests that newborns, particularly those from compromised pregnancies, are at increased risk of brain damage due to low neurosteroid levels. We believe that certain commonly used steroid therapies may also lower steroid levels in the brain and result in increased vulnerability to brain damage during birth or in the early neonatal period. Alternatively, we propose that replacement of neurosteroid precursors in the newborn may raise brain neurosteroid levels and protect against brain damage. In the proposed studies we will evaluate treatments that can raise the concentration of steroids and determine the best strategy for reducing brain injury following complications during pregnancy, at birth and during the early newborn period. This work will determine the best therapeutic approaches for maximising neurosteroid-induced brain protection and for reducing the risk of brain damage.Read moreRead less
Neuroactive Steroids In The Developing Brain: Potential For Preventing Perinatal Brain Damage
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Complications during pregnancy, birth asphyxia or premature birth can lead to serious neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neuroactive steroids are a group of neuromodulators that are derived from the hormone progesterone. These steroids fall into two groups, those that appear to protect brain cells from damage caused by an inadequate supply of oxygen and those that may increase cell death. We have shown tha ....Complications during pregnancy, birth asphyxia or premature birth can lead to serious neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neuroactive steroids are a group of neuromodulators that are derived from the hormone progesterone. These steroids fall into two groups, those that appear to protect brain cells from damage caused by an inadequate supply of oxygen and those that may increase cell death. We have shown that protective neuroactive steroids are present in very large amounts in the fetal brain. Steroids produced by the placenta are converted to these neuroactive products by enzymes in the brain leading to the high levels that are seen during fetal life. Certain adverse conditions during pregnancy as well as preterm birth may cause marked changes in the balance of steroids that could increase susceptibility to brain injury. We have found that areas of the brain, where damage most often occurs, normally contain the highest amount of protective steroids, but only in late pregnancy. This suggests that disturbances that lower steroid production in these areas could contribute to the death of cells, particularly in mid-pregnancy and after premature birth. In the proposed studies, we will examine whether a toxic balance of steroids develops following adverse events in pregnancy as well as the areas of the brain where this is most pronounced. We will examine the changes in the expression of enzymes that can potentially cause the accumulation of protective steroids in the brain. We will then examine treatments that can raise the concentration of steroids and determine which combination of steroids best reduces cell death and brain injury following complications during pregnancy. The findings of this work will indicate the best therapeutic approach that may be adopted to modify the concentration of certain steroids so as to reduce the risk of brain damage in the fetus and neonate.Read moreRead less
Why Does Early Life Stress Aggravate Limbic Epileptogenesis?
Funder
National Health and Medical Research Council
Funding Amount
$540,116.00
Summary
High rates of anxiety and depression occur in individuals with temporal lobe epilepsy (TLE), the most common form of focal epilepsy in adults. Rats that have experienced early life stress show increased anxiety, decreased seizure thresholds and accelerated epilepsy as adults. We have important leads to mechanisms. The proposed study will better understand the mechanisms connecting early life stress and psychiatric disease to adult TLE, and to test interventions that may counteract these effects.
Fibre-Polymer Composites With Graded Microstructure. This project concerns the development of a novel fibre-polymer functionally graded composite material that mimics the structure of the spinal disk. The spinal disk comprises a soft core (nucleus) and a tough fibrous periphery (annulus). The graded composite approach of this proposal represents a significant advance over spinal fusion, and over the current generation of spinal disk protheses (metal plates with springs/polymers as shock absorber ....Fibre-Polymer Composites With Graded Microstructure. This project concerns the development of a novel fibre-polymer functionally graded composite material that mimics the structure of the spinal disk. The spinal disk comprises a soft core (nucleus) and a tough fibrous periphery (annulus). The graded composite approach of this proposal represents a significant advance over spinal fusion, and over the current generation of spinal disk protheses (metal plates with springs/polymers as shock absorbers). Chronic back pain affects a significant proportion of the population and is primarily caused by failure of the spinal disk. Therefore a strong social and economic imperative exists to develop engineering solutions to this problem.Read moreRead less
Formation of bone-like materials for bone repair and regeneration. A successful outcome for this project would lead to the production and application of new bone-like calcium phosphate materials. Enhanced bioactivity of this material would lead to higher but controlled rates of calcium phosphate release. An understanding of the formation process of these materials and the controlled release of calcium phosphates has the potential to slow the development of metabolic diseases such as osteoporosis ....Formation of bone-like materials for bone repair and regeneration. A successful outcome for this project would lead to the production and application of new bone-like calcium phosphate materials. Enhanced bioactivity of this material would lead to higher but controlled rates of calcium phosphate release. An understanding of the formation process of these materials and the controlled release of calcium phosphates has the potential to slow the development of metabolic diseases such as osteoporosis. The WHO reports that osteoporosis is the second largest health care problem world-wide. In 2002, 44 million people in the USA were estimated to be at risk. This and similar figures in Australia and around the world emphasize the urgency of understanding and appropriately combating weak bone degenerative diseases.Read moreRead less
Evaluating the impact of obesity on knee load over time in those who have undergone optimal surgical re-alignment after total knee replacement . This project investigates the impact of obesity on alignment and knee load over time in those who have undergone total knee replacement. This information is critical for understanding whether obesity results in increasing knee load after surgery which can lead to more rapid wearing of the knee surfaces and an earlier need for revision surgery.
Molecular mechanisms of stem cell self-renewal. Muscle growth and regeneration is critically dependent on its stem cell compartment. We have discovered that the p38 MAPK pathway is essential for stem cell self-renewal in the C2C12 myogenic cell line. This proposal seeks to understand the molecular basis of stem cell self-renewal in skeletal muscles, data that may be applicable to many stem cell systems, and to the enormous promise of stem cell therapies for injury and diseases of the aged. We wi ....Molecular mechanisms of stem cell self-renewal. Muscle growth and regeneration is critically dependent on its stem cell compartment. We have discovered that the p38 MAPK pathway is essential for stem cell self-renewal in the C2C12 myogenic cell line. This proposal seeks to understand the molecular basis of stem cell self-renewal in skeletal muscles, data that may be applicable to many stem cell systems, and to the enormous promise of stem cell therapies for injury and diseases of the aged. We will attempt to alter the balance of stem cell production by enforced p38 expression, and take microarray and proteomics approaches to define stem cell pathways.Read moreRead less
Intracellular calcium in intact muscle during fatigue and stretch-induced damage. Confocal microscopes can investigate intact tissues during normal function. We will develop and apply this novel approach to muscle. We expect this new approach to become a fundamental new tool for exploring muscle function under near normal conditions. Muscle pain and weakness are common disabilities in humans and we expect this new approach to provide insights into the causes and treatment of these common cond ....Intracellular calcium in intact muscle during fatigue and stretch-induced damage. Confocal microscopes can investigate intact tissues during normal function. We will develop and apply this novel approach to muscle. We expect this new approach to become a fundamental new tool for exploring muscle function under near normal conditions. Muscle pain and weakness are common disabilities in humans and we expect this new approach to provide insights into the causes and treatment of these common conditions.Read moreRead less
Development of a Prothrombogenic Bone Graft Substitute. The clinical demand for bone is massive and to counter this bone can be either harvested from the patient or bone substitutes are used. The success or failure of a bone substitute is determined the instant it come into contact with blood. The surfaces of traditional biomaterials induce a foreign body reaction. The aim of this project is to test the bone forming capacity of a biomaterial that is optimised to produce a natural response from ....Development of a Prothrombogenic Bone Graft Substitute. The clinical demand for bone is massive and to counter this bone can be either harvested from the patient or bone substitutes are used. The success or failure of a bone substitute is determined the instant it come into contact with blood. The surfaces of traditional biomaterials induce a foreign body reaction. The aim of this project is to test the bone forming capacity of a biomaterial that is optimised to produce a natural response from the blood. This response will lead to the formation new viable tissue and eventually bone. Such a material will cause faster bone healing, less pain from graft sites, shorter hospital stays and shorter waiting lists. Read moreRead less