Investigation Of A Novel Sympathetic Vasomotor Pathway
Funder
National Health and Medical Research Council
Funding Amount
$354,586.00
Summary
Blood pressure is regulated by sympathetic nerves to the heart and blood vessels, and it is believed that overactive sympathetic nerves contribute to many cases of hypertension. Overactive sympathetic nerves also contribute to, and worsen the disease process, in heart failure as well as other cardiovascular diseases. The regulation of sympathetic nerves is thus central to the understanding and treatment of cardiovascular disorders. The present proposal is specifically relevant to the hypertensio ....Blood pressure is regulated by sympathetic nerves to the heart and blood vessels, and it is believed that overactive sympathetic nerves contribute to many cases of hypertension. Overactive sympathetic nerves also contribute to, and worsen the disease process, in heart failure as well as other cardiovascular diseases. The regulation of sympathetic nerves is thus central to the understanding and treatment of cardiovascular disorders. The present proposal is specifically relevant to the hypertension which accompanies airway obstruction during sleep (obstructive sleep apnoea - OSA). We plan to study a novel class of sympathetic nerves ('accessory' sympathetic nerves), which are likely to be centrally involved in the hypertension of OSA, and probably also other conditions where sympathetic nerve activity is pathologically raised. 'Accessory' sympathetic nerves can cause a long-lasting amplification of the activity in the 'regular' sympathetic nerve pathway, enhancing its actions on the heart and blood vessels. The brain pathways that drive 'accessory' sympathetic nerves are essentially unknown. We seek to find out those pathways, study how they amplify the activity in the 'regular' pathway and explore their significance in an animal model of OSA. The outcomes of this study will be first, essential basic knowledge of a novel, but probably important, mechanism whereby the brain controls the cardiovascular system in health and disease. Second, the relevance of that mechanism to a specific type of neurogenic hypertension will have been defined.Read moreRead less
How Does The Central Respiratory Generator Amplify Sympathetic Activity In Hypertension?
Funder
National Health and Medical Research Council
Funding Amount
$290,113.00
Summary
High blood pressure causes many life-threatening cardiovascular diseases, including heart failure and stroke. The cause of most high blood pressure is not known. Using an animal model of high blood pressure we have shown that an interaction, in the brain, between the nerve pathways that generate respiratory activity and regulate blood pressure is altered. This occurs early in life and our evidence strongly suggests this may be a cause of high blood pressure.
Nerve pathways exist that carry information from the highest parts of the brain to the peripheral hearing organ, the inner ear. These descending control pathways have the potential to affect the hearing process in a number of ways; protecting from loud sounds, improving the detection of signals in noisy backgrounds, selecting stimuli of interest and regulating a variety of aspects of inner ear function. Abnormal function of these pathways can affect hearing sensitivity and may be important in ph ....Nerve pathways exist that carry information from the highest parts of the brain to the peripheral hearing organ, the inner ear. These descending control pathways have the potential to affect the hearing process in a number of ways; protecting from loud sounds, improving the detection of signals in noisy backgrounds, selecting stimuli of interest and regulating a variety of aspects of inner ear function. Abnormal function of these pathways can affect hearing sensitivity and may be important in phenomena such as tinnitus and other disorders of hearing. This project will investigate the subtle effects that selective activation of these pathways has on inner ear function and will attempt to unravel the different influences that subcomponents of the pathways have on the different aspects of hearing.Read moreRead less
Respiratory Modulation Of RVLM Premotor Neurons: Role In The Sympathetic Over-activity Of Hypertension.
Funder
National Health and Medical Research Council
Funding Amount
$338,605.00
Summary
Hypertension is a common health disorder in all societies and is a major risk factor for the development of life threatening cardiovascular diseases, including heart failure and stroke. Whilst some effective therapies are available, many patients are not adequately treated or have reduced quality of life due to serious side effects. There is a great need for alternative therapies. The central nervous system is clearly involved in hypertension although the level of that involvement is not well un ....Hypertension is a common health disorder in all societies and is a major risk factor for the development of life threatening cardiovascular diseases, including heart failure and stroke. Whilst some effective therapies are available, many patients are not adequately treated or have reduced quality of life due to serious side effects. There is a great need for alternative therapies. The central nervous system is clearly involved in hypertension although the level of that involvement is not well understood- i.e. is it a causal factor or just a contributor to the maintenance of established hypertension? The experiments outlined in this application are based on the observation that modulation of nervous activity to blood vessels is more influenced by the respiratory system in people with high blood pressure, than in normotensive people. We aim to test whether this increased respiratory modulation might be involved in the generation of the high blood pressure.Read moreRead less
Peripheral Mechanisms Involved In Autonomic Hyperreflexia
Funder
National Health and Medical Research Council
Funding Amount
$229,917.00
Summary
Bladder distension or minor unheeded injuries below the lesion in spinally injured people often lead to episodes of high blood pressure that may cause stroke or death. These events require emergency hospitalization and are expensive as well as dangerous. After spinal injury, the control of sympathetic nerves that supply arteries and regulate blood pressure is lost. However, the nerves below the injury remain in place and the spinal cord below the lesion contains connections that can activate the ....Bladder distension or minor unheeded injuries below the lesion in spinally injured people often lead to episodes of high blood pressure that may cause stroke or death. These events require emergency hospitalization and are expensive as well as dangerous. After spinal injury, the control of sympathetic nerves that supply arteries and regulate blood pressure is lost. However, the nerves below the injury remain in place and the spinal cord below the lesion contains connections that can activate them. Signals from the bladder or skin enter the remaining lower part of the spinal cord and activate the sympathetic supply generating a rise in blood pressure. This project will test the hypothesis that increased sensitivity of arteries to the chemicals released from the sympathetic nerves leads to excessive vessel constriction, contributing to the exaggerated increase in pressure. We will investigate arteries removed from rats with experimental spinal transection. We will test the contractions of the arteries (a) to sympathetic nerve stimulation and (b) to the chemicals noradrenaline, adenosine 5'-triphosphate (ATP) and neuropeptide Y that are normally released during nerve activity. We will determine whether release of noradrenaline and ATP from nerves is normal or augmented using electrochemical and electrophysiological techniques. We will compare the responses with those in normal arteries, those in arteries whose nerves have been silenced by removing all connections from the spinal cord and those in arteries that have lost all their nerve supply. This will enable us to identify whether the mechanisms for release of transmitter substances are modified and whether the arterial muscle is hypersensitive to these substances. The results will help in the design of safer treatment for these potentially lethal emergencies in spinal patients.Read moreRead less
Biomathematical Analysis Of Cell Invasion: Migration Of Neural Crest Cells To Form The Enteric Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$449,484.00
Summary
Extending scientific studies to a mathematical level is the way to produce deep understanding and control. Mathematics has been applied less to biology, particularly the biology of development, than to other branches of science, no doubt due to the innate complexity and technical difficulties of seeing and measuring what is actually going on. Labelling, imaging and computational tools to visualise biological processes are only now becoming available. To build our bodies during embryonic developm ....Extending scientific studies to a mathematical level is the way to produce deep understanding and control. Mathematics has been applied less to biology, particularly the biology of development, than to other branches of science, no doubt due to the innate complexity and technical difficulties of seeing and measuring what is actually going on. Labelling, imaging and computational tools to visualise biological processes are only now becoming available. To build our bodies during embryonic development, cells must move; this is called cell migration. The same process occurs throughout life in wound repair. Uncontrolled migration is the hallmark of malignant cancers, where it is called invasion. The molecular mechanisms in cells that allow them to move are just beginning to be understood. However, the big questions determining the general rules of migration are more difficult to approach. Here are some examples of such questions. When to migrate? Where to migrate to? Which pathways? How many cells to migrate? How far? How fast? How to stop? Such simple questions are still unanswered. We are pioneering a novel and unique approach combining imaging of real cells migrating in real tissues (digital time-lapse movies) with mathematical modelling to understand the driving forces of cell migration-invasion. This technology is here applied to a particular example of cell migration where precursor nerve cells migrate all the way along the length of the gastro-intestinal tract in early development. This process gives rise to fatal birth defects associated with migration failure. The development of the nervous system in the gut has features in common with all other migrations and invasions, normal and pathological. A much more profound knowledge of the big picture of the developmentally and clinically crucial process of cell migration-invasion will emerge from this marriage of biological experimentation and mathematical modelling.Read moreRead less
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
ORIGIN AND REGULATION OF VAGAL PREGANGLIONIC NEURON SUBTYPES CONTROLLING AIRWAY SMOOTH MUSCLE TONE
Funder
National Health and Medical Research Council
Funding Amount
$438,700.00
Summary
The primary role of the airways is to allow the exchange of oxygen and carbon dioxide between the environment and the lungs. However, the airways are not merely a series of static tubes, but rather their size (or caliber) is subject to breath-by-breath alterations, thereby regulating gas exchange to match the body's demands. Regulation of airway caliber is achieved largely by subconscious changes in the tone of the muscle lining the airway wall. Airway muscle tone is primarily under the control ....The primary role of the airways is to allow the exchange of oxygen and carbon dioxide between the environment and the lungs. However, the airways are not merely a series of static tubes, but rather their size (or caliber) is subject to breath-by-breath alterations, thereby regulating gas exchange to match the body's demands. Regulation of airway caliber is achieved largely by subconscious changes in the tone of the muscle lining the airway wall. Airway muscle tone is primarily under the control of the parasympathetic division of the autonomic nervous system. Two distinct types of parasympathetic nerves innervate the airways: One type employs the neurotransmitter acetylcholine which causes airway muscle to contract and the airways to constrict, while the other type employs nitric oxide which evokes airway dilatation. The normal regulation of airway caliber is altered in a variety of inflammatory airways diseases. In asthma and chronic obstructive pulmonary disease (COPD) there is an increase in airway muscle tone (airway constriction) which compromises the normal movement of gasses and contributes to the morbidity and mortality of the diseases. There is a growing body of evidence to suggest that exaggerated airway muscle tone may in part result from dysfunction of either the contractile or relaxant parasympathetic nerves innervating the airways. However, at present very little is known about the parasympathetic pathways regulating airway caliber. A complete understanding of the mechanisms controlling airway smooth muscle tone is therefore essential to fully understanding possible role of autonomic dysfunction in the pathogenesis of obstructive airways diseases. The aim of this grant is to better define the physiological and anatomical properties of airway parasympathetic nerves in the brain stem.Read moreRead less
Parkinson's Disease is caused by injury to a group of brain cells called the Basal Ganglia. Our current ideas about how this part of the brain works is dominated by a well know theory. This theory requires that the output pathway of the basal ganglia to have a negative or inhibitory influence on its target. However there are numerous reasons why this would be unlikely, including some recent evidence from experiments in our laboratory. The purpose of this study is to undertake an extensive re exa ....Parkinson's Disease is caused by injury to a group of brain cells called the Basal Ganglia. Our current ideas about how this part of the brain works is dominated by a well know theory. This theory requires that the output pathway of the basal ganglia to have a negative or inhibitory influence on its target. However there are numerous reasons why this would be unlikely, including some recent evidence from experiments in our laboratory. The purpose of this study is to undertake an extensive re examination of the output paths of the Basal Ganglia. If our suspicions are correct, it will lead to a review of the whole way in which we think the Basal Ganglia works.Read moreRead less