Identification Of Heterogeneity In Vasodilator Function In Human And Rat Resistance Vessels: Potential Drug Targets?
Funder
National Health and Medical Research Council
Funding Amount
$595,330.00
Summary
The balance between the ways that blood vessels decrease in size (constrict) and increase in size (dilate) determine how blood vessels normally function. There are many differences in the ways that blood vessels control this balance in different parts of the body. Such differences are altered in vascular diseases, such as hypertension and diabetes, which are prevalent in obesity, such that constriction generally outweighs dilation. However, what these differences are and how they occur are not w ....The balance between the ways that blood vessels decrease in size (constrict) and increase in size (dilate) determine how blood vessels normally function. There are many differences in the ways that blood vessels control this balance in different parts of the body. Such differences are altered in vascular diseases, such as hypertension and diabetes, which are prevalent in obesity, such that constriction generally outweighs dilation. However, what these differences are and how they occur are not well understood. While current drugs for treating vascular disease either reduce vessel constriction or increase dilation, they are not specific for individual arteries; a situation that would allow us to control vascular diseases in a very specific manner. Recently, we have described differences between the ways that individual vessels are controlled. These changes relate to differences in the way that different vessels dilate. AIMS - To further understand normal blood vessel function and the changes that occur in blood vessels in cardiovascular disease, with a focus on the ways that blood vessels dilate in normal states and in obesity-related diseases, such as in hypertension and diabetes. - The eventual aim is to identify the specific ways that arteries function, so that artery-specific drug targets can be identified to treat disease-related changes in cardiovascular disease in a very specific manner. EXPECTED OUTCOMES This project will contribute to understanding blood vessel function in health and disease. The expected eventual outcome is the identification of the mechanisms that underlie the function of different arteries in different parts of the body, so that specific individual vessel function can be targeted to treat vascular disease. Additionally, this work will also verify the relevance of the diet-induced obesity animal model, in terms of the characteristics and causes of human obesity and related cardiovascular disease.Read moreRead less
An Implementation Trial Of A Telephone-based Care Management Program For Patients Following Myocardial Infarction
Funder
National Health and Medical Research Council
Funding Amount
$641,656.00
Summary
We are trialling the implementation of an innovative telephone-delivered program for managing people who have had a heart attack. Cardiac rehabilitation programs are generally based in hospitals in Australia and people have to be able to attend the programs when they are offered. Even though such programs have been shown to be very effective in improving outcomes after a heart attack, at least 85% of Australians after a heart attack are either unable to access and-or unable to attend such progra ....We are trialling the implementation of an innovative telephone-delivered program for managing people who have had a heart attack. Cardiac rehabilitation programs are generally based in hospitals in Australia and people have to be able to attend the programs when they are offered. Even though such programs have been shown to be very effective in improving outcomes after a heart attack, at least 85% of Australians after a heart attack are either unable to access and-or unable to attend such programs due to transport and many other barriers. So, there is an urgent need to identify new, effective, and affordable ways of delivering cardiac rehabilitation programs to people after a heart attack. The proposed telephone-delivered program will be particularly appropriate for disadvantaged people, such as those living in rural and remote areas as well as Indigenous Australians, who do not currently have access to hospital-based cardiac rehabilitation programs. People who have had a heart attack will be recruited from three of Brisbane's largest public teaching hospitals, and will then be randomly assigned to the telephone-delivered cardiac rehabilitation program (Care Management Intervention group) or to a control or Usual Care group. The Care Management Intervention group will receive regular telephone calls from a highly qualified 'Care Manager' based at the renowned National Heart Foundation of Australia telephone support service, 'Heartline'. The Care Manager will help people to manage their heart condition and prevent the reoccurrence of further heart problems. People will also be encouraged to make necessary lifestyle and behavioural changes with the assistance of the Care Manager and some Heart Foundation educational and interactive resources to record their progress. We expect that the program or Care Management Intervention group will have better health outcomes than the control or Usual Care group at 6 and 12 months follow up.Read moreRead less
We will conduct a survey of respiratory symptoms, lung function, smoking status, occupational exposures, and other risk factors among 3200 people aged 40 years and over living in five Australian communities: Melbourne, Sydney, Tasmania, Busselton (WA), and the Kimberley region (WA). In the Kimberley we will survey 400 Aboriginal people and 400 non-Aboriginal people. We will use a survey methodology that has been developed by an international expert panel and has been implemented in many other co ....We will conduct a survey of respiratory symptoms, lung function, smoking status, occupational exposures, and other risk factors among 3200 people aged 40 years and over living in five Australian communities: Melbourne, Sydney, Tasmania, Busselton (WA), and the Kimberley region (WA). In the Kimberley we will survey 400 Aboriginal people and 400 non-Aboriginal people. We will use a survey methodology that has been developed by an international expert panel and has been implemented in many other countries (in North and South America, Asia, and Europe). This study will provide the first nationally-representative information on the burden of chronic obstructive pulmonary disease (COPD) and the opportunities for health gain by improving the management of this illness. In Australia, COPD is a relatively silent and under-recognised disease but nevertheless is the third most important contributor to the burden of disease and the third leading cause of hospital admission as well as being the underlying cause of 4.2% of all deaths. The information we will collect is needed to form a basis for prevention and disease management interventions to reduce the burden of COPD, particularly among population sub-groups who are disproportionately affected, either due to greater exposure to risk factors (mainly tobacco smoking and occupation), greater susceptibility, under-recognition and under-diagnosis, or inadequate disease management. Importantly, the study will serve to raise awareness about the hazards of smoking for all Australians. By identifying target groups, prevalent exposures and management deficiencies, it will lead the way towards policy-relevant randomised controlled trials testing community-based interventions to prevent COPD and-or manage it more effectively. The information collected will help advance knowledge of the prevalence, burden and treatment of COPD that will be relevant to communities throughout the world.Read moreRead less
Drug-induced Immune Thrombocytopenia: Understanding The Disease Mechanisms Is The Key To Better Treatment
Funder
National Health and Medical Research Council
Funding Amount
$509,550.00
Summary
Many very commonly used medications cause an allergic reaction in a small number of patients that receive them. The allergic reaction results in platelets being destroyed and puts the patients at risk of bleeding. The patient recovers slowly if the drug is stopped but there is no other treatment and no way to reverse the effect quickly if the patient starts to bleed. This project will try to understand the mechanism of the condition and test a potential treatment.
Targeting PI3K-regulated MicroRNAs To Treat Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$532,593.00
Summary
Current therapeutics largely delay heart failure progression rather than regressing it. New therapeutic strategies with the capability of improving function of the failing heart are thus greatly needed. The primary goal of this study is to determine whether novel regulatory genes can enhance cardiac function in a setting of heart failure. Ultimately, technologies that target these genes may lead to innovative pharmacotherapies in the clinical management of heart failure.
An Examination Of Motor Functioning In Autism And Asperger's Disorder: An Analysis Of Gait & Cortical Brain Activity.
Funder
National Health and Medical Research Council
Funding Amount
$120,220.00
Summary
Autism is a developmental disorder characterised by a triad of deficits: delayed and atypical language development, impaired development of social skills, and ritualistic and stereotypic behaviour. Although not part of the standard diagnosis, movement disorders and gait abnormalities have been clinically observed in autism similar to those seen in Parkinson's disease. In addition, individuals with Asperger's disorder may appear more clumsy, have a stiff or awkward way of walking, and exhibit poo ....Autism is a developmental disorder characterised by a triad of deficits: delayed and atypical language development, impaired development of social skills, and ritualistic and stereotypic behaviour. Although not part of the standard diagnosis, movement disorders and gait abnormalities have been clinically observed in autism similar to those seen in Parkinson's disease. In addition, individuals with Asperger's disorder may appear more clumsy, have a stiff or awkward way of walking, and exhibit poor coordination in posture and gesture. It has been suggested that there is disruption within the basal-ganglia-thalamocortical circuitry (the region connecting the frontal and sub-cortical structures), which may cause the motor dysfunction seen in autism and Asperger's disorder. Few studies have attempted to isolate particular stages of motor functioning which may account for the coordination and motor delay observed clinically in autism and Asperger's disorder. A recent study of ours found evidence to suggest that motor planning deficiencies may account for the 'clumsy' movement patterns frequently reported in the autism - Asperger's disorder literature. Therefore, the aim of this research is to provide a comprehensive neurobehavioural and neurophysiological analysis of motor functioning in young people with autism and Asperger's disorder to further examine the exact stages of motor processing which are deficient in these disorder groups. Recent retrospective studies have shown that even as infants children with autism exhibit clear features of motor disturbance, which, if detected and clearly defined, could advance early diagnosis. In addition to advancing the clinical definition of autism and Asperger's disorder, a careful examination of motor disturbance may also illuminate the neurobiological underpinnings of these disorders.Read moreRead less
Role Of Transition Metal Ions And Redox Activity In The Development Of Atherosclerotic Plaques
Funder
National Health and Medical Research Council
Funding Amount
$196,018.00
Summary
Metal ions such as iron and copper have been reproted to be present in the lesions present in diseased human arteries and it has been suggested that these metal ions contribute to the development of atherosclerosis (hardening of the arteries) via their ability to catalyse the formation of highly reactive molecualr fragments called free radicals. Though metal ions are known to catalyse such reactions in test-tube experiments, both the presence of metal ions in diseased arteries and their ability ....Metal ions such as iron and copper have been reproted to be present in the lesions present in diseased human arteries and it has been suggested that these metal ions contribute to the development of atherosclerosis (hardening of the arteries) via their ability to catalyse the formation of highly reactive molecualr fragments called free radicals. Though metal ions are known to catalyse such reactions in test-tube experiments, both the presence of metal ions in diseased arteries and their ability to generate free radicals is controversial. This study will employ a novel, minimally-invasive, technique to assess the nature and quantity of metal ions present in well-defined human and animal lesions at different stages of lesion development. The ability of these metal ions to catalyse free radical formation from components present in the artery wall will also be assessed. The release of these metal ions from the artery wall to added organic molecules will be assessed as this might minimise their potential to cause damage, and provide a possible therapeutic strategy. These studies will therefore provide valuable information as to the significance and role of reactive metal ions in the development of human artery disease and the possible prevention, or minimisation, of such processes.Read moreRead less
How Do Thick Airway Walls Affect Airway Hyperresponsiveness In Asthma?
Funder
National Health and Medical Research Council
Funding Amount
$382,538.00
Summary
Asthmatic airways narrow too easily, a characteristic called airway hyperresponsiveness (AHR). To understand the cause of asthma we need to understand the cause of AHR. Thickened airway walls could amplify airway narrowing and increase AHR. However, thick airway walls are also stiff, and stiff walls could reduce narrowing and AHR. This project will examine the relationships between AHR and airway wall thickness and stiffness during and after treatment that reduces airway wall thickness.
THE BAROREFLEX IN SNORING AND THE OBSTRUCTIVE SLEEP APNOEA HYPOPNOEA SYNDROME
Funder
National Health and Medical Research Council
Funding Amount
$436,261.00
Summary
The obstructive sleep apnoea hypopnoea syndrome (OSAHS) refers to a condition in which throat blockage occurs during sleep leading to breathing difficulties, including snoring and cessation of breathing for short periods of time. OSAHS is amongst the commonest of chronic disorders of adult males, occuring in 5% of men over the age of 45 years. It is now recognised that one of the major complications of OSAHS is the development of high blood pressure and heart disease. In the proposed studies, we ....The obstructive sleep apnoea hypopnoea syndrome (OSAHS) refers to a condition in which throat blockage occurs during sleep leading to breathing difficulties, including snoring and cessation of breathing for short periods of time. OSAHS is amongst the commonest of chronic disorders of adult males, occuring in 5% of men over the age of 45 years. It is now recognised that one of the major complications of OSAHS is the development of high blood pressure and heart disease. In the proposed studies, we will examine the proposal that snoring alone, without significant associated OSAHS, can also lead to high blood pressure in habitual snorers both awake and asleep. In particular, we will explore the hypothesis that chronic snoring transmits a pressure wave through the tissues of the neck to the carotid artery which is the main blood supply to the brain. We propose that the chronic vibration of this artery can alter pressure sensors in the artery wall, which then results in the persistance of high blood pressure. Our studies will help to prove that this is a mechanism whereby both snoring and OSAHS may contribute to the development of high blood pressure. The recognition of snoring as an independent risk factor for high blood pressure will clearly have important and wide ranging implications for the future management of snoring in the prevention of high blood pressure.Read moreRead less
Molecular Mechanisms Of Receptor Activation And Signalling
Funder
National Health and Medical Research Council
Funding Amount
$571,980.00
Summary
Fundamental to our ability to respond to both immediate and long-term environmental changes and stresses is the coordinated regulation of cellular functions by hormonal and neurotransmitter stimuli. The great majority of such stimuli are sensed by G-protein coupled receptors (GPCR), complex glycoprotein molecules on the surface of most cells that selectively bind and are activated by various hormones and neurotransmitters. Although GPCRs are a superfamily of proteins that now compromise several ....Fundamental to our ability to respond to both immediate and long-term environmental changes and stresses is the coordinated regulation of cellular functions by hormonal and neurotransmitter stimuli. The great majority of such stimuli are sensed by G-protein coupled receptors (GPCR), complex glycoprotein molecules on the surface of most cells that selectively bind and are activated by various hormones and neurotransmitters. Although GPCRs are a superfamily of proteins that now compromise several hundred distinct but structurally-related members, the molecular mechanisms involved in their activation and, thus, their regulation of vital cellular functions, remains unclear. Based on insights that we have gained from the development and characterisation of several alpha1-adrenergic receptor mutants, we have developed a model of receptor activation. In this application we are proposing to further test and to extend the hypotheses underlying this model. Importantly, the functions regulated by GPCR include vital responses, such as the maintenance of circulatory homeostasis by augmenting heart pump function and by constricting vascular smooth muscle to maintain blood pressure. In addition, disordered cellular regulation by GPCR has been implicated in a wide variety of diseases, including hypertension, congestive heart failure and cardiac hypertrophy. Thus, the studies detailed here to further understand the molecular mechanisms of receptor activation have broad implications for our knowledge of critical physiological control systems, and may lead to novel therapeutic approaches to treat a variety of diseases.Read moreRead less