Elucidation Of The Molecular Requirements Of The Low Affinity 'state' Of The Beta1-adrenoceptor
Funder
National Health and Medical Research Council
Funding Amount
$535,500.00
Summary
Beta-blockers are used for the management of cardiovascular diseases including heart failure, ischaemic heart disease and high blood pressure. Beta-blockers mostly work by blocking the effects of a naturally occuring chemical called noradrenaline. Beta-blockers can be used to prevent noradrenaline induced increases in the rate and force of human heart contraction. We have discovered that one group of beta-blockers exemplified by CGP 12177 has the remarkable property of not only being able to blo ....Beta-blockers are used for the management of cardiovascular diseases including heart failure, ischaemic heart disease and high blood pressure. Beta-blockers mostly work by blocking the effects of a naturally occuring chemical called noradrenaline. Beta-blockers can be used to prevent noradrenaline induced increases in the rate and force of human heart contraction. We have discovered that one group of beta-blockers exemplified by CGP 12177 has the remarkable property of not only being able to block beta-receptors but they can also stimulate them at higher concentrations. Thus low concentrations block the effects of noradrenaline, but higher concentrations stimulate the receptor. More puzzling is that the stimulant effects of this group of beta-blockers cannot be easily blocked. To explain this we hypothesize that human beta-receptors can exist in two different 'states'. One 'state' can be stimulated by noradrenaline and blocked by low concentrations of beta-blockers such as propranolol and CGP 12177. Another 'state' of the same receptor is resistant to blockade by beta-blockers such as propranolol but can be stimulated by beta-blockers such as CGP 12177. This project seeks to investigate the molecular basis of the beta-adrenoceptor that is responsible for stimulant effects of beta-blockers. Specifically it explores the components of the beta-adrenoceptor that are critically and uniquely important for interacting with the stimulant beta-blockers. This project is an important increment in our laboratories research program to increase our understanding of the effects of beta-blockers. Our long term goal is to be able to develop beta-blockers that can block both states of the beta-adrenoceptor to provide a more effective block of the receptor and in particular for the improved management of heart failure.Read moreRead less
Contractile And Relaxant Effects Of B2- And B1-adrenoceptors In Human Heart: Blockade By A Third Generation B-blocker
Funder
National Health and Medical Research Council
Funding Amount
$136,320.00
Summary
The force and the duration of each heart beat can be modified in disease states affecting the heart. They can also be modified by chemicals which occur naturally in the body. Two of the most important naturally occurring chemicals which affect the function of the heart are (-)-noradrenaline and (-)-adrenaline. These chemicals and others which have been synthesized and optimized can also be used therapeutically. They work by activating proteins which occur on the cell surface, called b-adrenocept ....The force and the duration of each heart beat can be modified in disease states affecting the heart. They can also be modified by chemicals which occur naturally in the body. Two of the most important naturally occurring chemicals which affect the function of the heart are (-)-noradrenaline and (-)-adrenaline. These chemicals and others which have been synthesized and optimized can also be used therapeutically. They work by activating proteins which occur on the cell surface, called b-adrenoceptors. When activated, b-adrenoceptors cause an increase in the force of each heart beat and a reduction in the duration of each heart beat. This may be an advantage in conditions where the heart beat is too long. In this study we propose to map the biochemical pathways through which b-adrenoceptors affect each heart beat. The therapeutic management of heart failure has been revolutionized by the use of compounds which block b-adrenoceptors. One such drug, carvedilol is currently used in this country. The way in which it works may not be fully understood. In preliminary experiments we have identified a novel mechanism for carvedilol directly in human heart in which it may work and contribute to it's beneficial effects in the management of heart failure. Our studies will focus on this finding.Read moreRead less
Trajectories Between Childhood Internalising Behaviour Problems And Adolescent Depressive Symptoms
Funder
National Health and Medical Research Council
Funding Amount
$55,000.00
Summary
Depressive symptoms are known to escalate sharply through the adolescent years. Adolescents who experience an episode of depression are very likely to experience further mental illness as adults. Efforts to prevent depressive illness may be advanced by research delineating the factors and processes implicated in the early emergence of depressive symptoms. To advance such an understanding this project will analyse data collected, in part, through NHMRC support to Australian Temperament Project (A ....Depressive symptoms are known to escalate sharply through the adolescent years. Adolescents who experience an episode of depression are very likely to experience further mental illness as adults. Efforts to prevent depressive illness may be advanced by research delineating the factors and processes implicated in the early emergence of depressive symptoms. To advance such an understanding this project will analyse data collected, in part, through NHMRC support to Australian Temperament Project (ATP) researchers. The ATP data will be used to examine factors associated with the development and progression of depressive symptoms from childhood to adolescence. The ATP data set includes detailed longitudinal data collected from multiple sources (parents, teachers and youth) concerning child and adolescent temperament, behavioural problems, mother-child relations, health, depressive symptoms, school achievement, school adjustment, social skills, peer relationships, parenting practices, stressful life events, and sociodemographic factors. Of an original sample of 2443 enrolled in the cohort in 1983 (aged 4-8 months) a subsample of 1,350 adolescents should complete the data collection due in 2000 (age 17-18). Through the analysis of ATP data proposed in this application, models will be developed to explain the risk and resiliency processes in childhood and early adolescence influencing the development and course of adolescent depression, for different subgroups of adolescents. To achieve this objective, analyses will: 1. identify groups who have differing trajectories from childhood internalising behaviour problems to adolescent depressive symptoms; 2. compare groups to identify factors that contribute to the progression from internalising behaviour problems to depressive symptoms, while also identifying factors which appear to impede such progression and; 3. compare groups to identify factors associated with transient versus persistent depressive symptoms in adolescence.Read moreRead less
Frontal-striatal-parietal Activation In Children With ADHD, Combined Type: A Functional Magnetic Resonance Imaging Study
Funder
National Health and Medical Research Council
Funding Amount
$91,750.00
Summary
Attention Deficit Hyperactivity Disorder, combined type (ADHD-CT) is a common neuropsychiatric disorder that has serious consequences for affected children's educational and social development and success in later life. Despite a large investment in research investigating aetiology and therapeutic strategies that arise from these aetiological investigations, ADHD-CT remains poorly understood and it is often viewed with therapeutic pessimism. Understanding the neurobiological basis of ADHD-CT is ....Attention Deficit Hyperactivity Disorder, combined type (ADHD-CT) is a common neuropsychiatric disorder that has serious consequences for affected children's educational and social development and success in later life. Despite a large investment in research investigating aetiology and therapeutic strategies that arise from these aetiological investigations, ADHD-CT remains poorly understood and it is often viewed with therapeutic pessimism. Understanding the neurobiological basis of ADHD-CT is of tremendous importance for the development of more specific and targeted medication and-or psychological treatments and, ultimately, to obtain the best clinical outcome for individual children with ADHD-CT. We have previously examined the function of frontal-striatal-parietal brain networks in adolescent boys with ADHD-CT, showing dysfunction of brain systems important for the control of visuospatial attention. In this project, we aim to examine whether these changes in frontal-striatal-parietal brain function also occur in pre-pubertal 8-12 year-old boys with ADHD-CT. This is important for two major reasons: Firstly, adolescents and young adults examined in previous brain imaging studies of ADHD-CT, including our own, are not truly representative of the core of the disorder, as ADHD-CT has its peak prevalence from 8 to 12 years of age. Secondly, by now comparing pre-pubertal ADHD-CT and healthy control children we can determine whether the changes in brain function we have previously identified represent developmental stage independent brain dysfunction that is characteristic of ADHD-CT.Read moreRead less
LONG TERM FUNCTIONAL ABILITY AND COSTS OF STROKE SUBTYPES.
Funder
National Health and Medical Research Council
Funding Amount
$270,604.00
Summary
Stroke is the third most common cause of death in Australia, and is more common in the older age groups. Because the population most at risk of developing stroke is growing faster than the rest of the population, it is likely that there will be a large increase in the number of strokes occurring in coming years. At 1 year after stroke about one-third of patients have died, a third remain severely disabled and a third recover with minimal disability. In Australia, there is little information on o ....Stroke is the third most common cause of death in Australia, and is more common in the older age groups. Because the population most at risk of developing stroke is growing faster than the rest of the population, it is likely that there will be a large increase in the number of strokes occurring in coming years. At 1 year after stroke about one-third of patients have died, a third remain severely disabled and a third recover with minimal disability. In Australia, there is little information on outcome beyond 1 year. It is thought that at 5 years after stroke about 55% of patients will die, and a further 10% will have another nonfatal stroke. Stroke is estimated to cost the community in excess of $1 billion a year. Little is known about the long-term costs of stroke to survivors and their relatives. These costs are likely to be substantial, and are likely to include costs related to hospitalisations, outpatient visits, general practitioner visits, medications, aids and community services. It is also likely that substantial informal care is provided by relatives and friends (e.g. assistance with shopping and personal care). The aim of this study is to assess the long-term outcome of patients with stroke. These will include measures of survival, stroke recurrence, and ability to perform usual daily activities. In addition, we aim to determine the long-term use of health care and community resources and the costs incurred by patients, their carers, and the community. Information on survival patterns, stroke recurrence and disability will provide information of great value for health service planning. Such information will also be useful to patients, their families, and medical staff who treat these patients. Information on the costs of stroke will provide the only information about the patterns of long-term health care and community resource use among stroke patients in Australia. This information will be useful for health service planning.Read moreRead less