Central Control Of Blood Pressure: Neurotransmitters, Receptors, Signal Transduction And Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$941,350.00
Summary
The way that the brain controls blood pressure is of crucial significance to our day-to-day survival. Nerves in the lower brain and spinal cord cause blood pressure to be maintained at appropriate levels for all types of daily activities ranging from sleep, when blood pressure is very low, to exercise when blood pressure can be very high. In hypertension, a disorder that afflicts around 10% of the community, blood pressure is elevated to an extent that damages organs such as the brain, heart, ki ....The way that the brain controls blood pressure is of crucial significance to our day-to-day survival. Nerves in the lower brain and spinal cord cause blood pressure to be maintained at appropriate levels for all types of daily activities ranging from sleep, when blood pressure is very low, to exercise when blood pressure can be very high. In hypertension, a disorder that afflicts around 10% of the community, blood pressure is elevated to an extent that damages organs such as the brain, heart, kidney and eye. It now appears that most cases of hypertension have as their basis a disorder of the way that the brain, through the sympathetic nervous system, controls the heart and blood vessels. Many different brain systems need to change the way that blood is distributed in the body at different times. For example, when we eat, blood goes preferentially to our gut; if we exercise, to our heart and muscles; if we are cold, to our skin and when we think, to our brain. This specialised regulation of blood flow is accomplished by the interaction of nerves in the lower brain and spinal cord. It involves a vast array of special chemical messengers acting on specific receptors through different intracellular mechanisms and involving the turning on or off of genes. Only a few of these neurotransmitter systems are well understood. At the core of our proposal, we aim to determine which neurotransmitters systems are important for which cardiovascular functions. We anticipate that this new information will permit the development of new approaches to the management of hypertension. The reason for this is that since different pathways use different messenger systems, it should become possible to tailor therapy to suit hypertension without causing undesirable side-effects.Read moreRead less
Thioredoxin Interacting Protein: A Novel Regulator Of Angiogenesis And Impaired Neovascularisation In Diabetes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$292,639.00
Summary
Heart disease is the leading cause of death and treatment options such as bypass surgery are unsuitable for many sufferers, particularly those with diabetes. This project investigates the regulation of new blood vessel growth through the action of antioxidants and also examines the contribution of adult stem cells to this process. Regulating new blood vessel growth provides a novel means to overcome current problems in the management of both non-diabetic and diabetic patients with heart disease.
Molecular Mechanisms For The Cell-type Specific Regulation Of The Tissue-type Plasminogen Activator Gene
Funder
National Health and Medical Research Council
Funding Amount
$490,500.00
Summary
Tissue-type plasminogen activator (t-PA) is an important enzyme that is widely known for its ability to remove blood clots. More recently, t-PA has been shown to influence memory development and under pathological conditions can promote neuronal cell death. t-PA is produced by many cells including the endothelial cells that line the blood vessels, fibroblasts, as well as cells within the central nervous system. The t-PA gene is regulated very differently in these cell types and this project will ....Tissue-type plasminogen activator (t-PA) is an important enzyme that is widely known for its ability to remove blood clots. More recently, t-PA has been shown to influence memory development and under pathological conditions can promote neuronal cell death. t-PA is produced by many cells including the endothelial cells that line the blood vessels, fibroblasts, as well as cells within the central nervous system. The t-PA gene is regulated very differently in these cell types and this project will address the mechanisms underlying the cell-type specific regulation of the t-PA gene. Endothelial cells, fibroblasts and neuronal cell cultures will be used to study the regulation of t-PA expression. Information gained will not only add to the understanding of the broader field of gene regulation, but may also provide clues to manipulate the expression of the t-PA gene in different cells.Read moreRead less
A common medical problem is the inability to maintain normal blood pressure while standing. This can cause blackouts, falls and injury. The available medical treatment is very deficient, because the various body mechanisms at play are poorly understood, so it has not been possible to specifically target the root cause. This grant application aims to study patients with these “postural hypotension” disorders, to better understand how the problems develop, and consequently, to provide better medic ....A common medical problem is the inability to maintain normal blood pressure while standing. This can cause blackouts, falls and injury. The available medical treatment is very deficient, because the various body mechanisms at play are poorly understood, so it has not been possible to specifically target the root cause. This grant application aims to study patients with these “postural hypotension” disorders, to better understand how the problems develop, and consequently, to provide better medical treatment.Read moreRead less
Of Mice And Men: Assessing Dietary Proteins Role On Appetite Regulation, Obesity And Cardiovascular Risk
Funder
National Health and Medical Research Council
Funding Amount
$86,521.00
Summary
While the challenge of understanding and managing the global obesity epidemic is well recognised, the role that nutrition plays is more complex than at first glance. Dietary protein may be of central importance in managing weight and small changes in protein consumption may lead to large changes in energy intake and weight. We propose to look at the effects of dietary protein on appetite, its hormonal regulation, and on the risk of developing metabolic diseases such as diabetes.
Effects Of Ghrelin Receptor Ligands On Cardiovascular Function
Funder
National Health and Medical Research Council
Funding Amount
$516,207.00
Summary
Ghrelin is a hormone that is known to control food intake and growth hormone release. Our recent work shows that compounds that mimic ghrelin�s actions influence blood pressure by their effects in the brain, the spinal cord and on arteries. We will investigate the potential of such compounds to treat blood pressure disorders
Contribution Of The Central Nervous System To Peripheral Neural Control In Obesity And Diabetes.
Funder
National Health and Medical Research Council
Funding Amount
$454,691.00
Summary
Obesity and diabetes are becoming major worldwide public health problems. A characteristic of human obese diabetes is a marked increase in sympathetic nerve activity to the kidneys and to the muscle. The cause of this overactivity is unknown, but undoubtedly involves the central nervous system. Within the brain are a select group of regions that are able to directly influence the activation of the sympathetic nervous system. We suspect these areas to play a critical role in the overactivity of t ....Obesity and diabetes are becoming major worldwide public health problems. A characteristic of human obese diabetes is a marked increase in sympathetic nerve activity to the kidneys and to the muscle. The cause of this overactivity is unknown, but undoubtedly involves the central nervous system. Within the brain are a select group of regions that are able to directly influence the activation of the sympathetic nervous system. We suspect these areas to play a critical role in the overactivity of the sympathetic nerve activity in obese diabetics. Indeed, we believe that there are specific chemical messengers in these select brain areas that are normally finely balanced. In obesity - diabetes, this balance is disturbed. Finally, we hypothesise that exercise, which is known to have beneficial effects for obesity - diabetes, restores the balance of the neurochemicals and this contributes to the positive outcomes of exercise.Read moreRead less
Heart failure is a severely debilitating condition with a poor prognosis. It is characterized by retention of fluid and high nervous activity especially to the kidneys and the heart. Even with the best current treatment available, patients with heart failure still suffer from abnormally high nerve activity to the further detriment of this condition. The successful completion of this project will provide considerable insight into the role of the brain in the elevated nerve activity in heart failu ....Heart failure is a severely debilitating condition with a poor prognosis. It is characterized by retention of fluid and high nervous activity especially to the kidneys and the heart. Even with the best current treatment available, patients with heart failure still suffer from abnormally high nerve activity to the further detriment of this condition. The successful completion of this project will provide considerable insight into the role of the brain in the elevated nerve activity in heart failure. It will also provide us with a significant understanding of the role in reflex sympathetic nerve regulation of an important brain region known as the hypothalamic paraventricular nucleus (PVN). Our findings will help us understand the nature of the neurotransmitters contributing to the reflex nerve regulation and the specific neurons within the PVN involved. This knowledge could help us to identify novel potential therapeutic targets within the brain to alleviate the problems observed in heart failure.Read moreRead less
PCSK9 is an inhibitor of the receptor that is responsible for removing LDL (the bad cholesterol) from the circulation. We will study the molecular mechanisms that inhibit PCSK9 at the protein level. This study is needed to understand if drugs that inhibit PCSK9 will diminish the risk of developing heart disease in patients who do not respond well to existing treatments, for example those who already had a cardiovascular event or those with familial hypercholesterolemia.
Control Of The Cholesterol Esterification Cycle In Macrophages
Funder
National Health and Medical Research Council
Funding Amount
$150,660.00
Summary
Atherosclerosis is the disease which narrows arteries and causes heart attacks. It is the most important cause of death in Australia. Although certain treatments such as lowering blood cholesterol reduce the incidence of heart attack, the current mortality from this conditions indicates that there is a great need to improve our understanding and treatment of atherosclerosis. In atherosclerotic arteries, cells called macrophages contain excess cholesterol in the form of cholesteryl ester droplets ....Atherosclerosis is the disease which narrows arteries and causes heart attacks. It is the most important cause of death in Australia. Although certain treatments such as lowering blood cholesterol reduce the incidence of heart attack, the current mortality from this conditions indicates that there is a great need to improve our understanding and treatment of atherosclerosis. In atherosclerotic arteries, cells called macrophages contain excess cholesterol in the form of cholesteryl ester droplets. It appears that human cells are very inefficient at clearing such cholesteryl esters, and this may explain why atherosclerosis is difficult to treat. In this proposal we will investigate how macrophages metabolise these cholesteryl esters and how this process can be stimulated. The results of this study should enable novel treatments of this serious condition to be developed.Read moreRead less