Roles Of The Peptide Hormone, Ghrelin, In The Spinal Cord
Funder
National Health and Medical Research Council
Funding Amount
$414,326.00
Summary
This study investigates the control of internal organs of the body, the heart, blood vessels, intestine and bladder. We have made the new and surprising discovery that ghrelin, previously known to be a hormone, is probably also a neurotransmitter in the spinal cord. This raises the possibility that drugs that act on ghrelin receptors in the spinal cord could be used to treat high blood pressure or other problems of internal organs.
Changes In Pelvic Autonomic Neurons After Spinal Nerve Injury
Funder
National Health and Medical Research Council
Funding Amount
$176,734.00
Summary
This project is about the effects of spinal injury on autonomic neurons that control the bladder, lower bowel and reproductive organs. One of the consequences of some types of spinal injury is that there are no signals being sent from the spinal cord to the nerve cells outside the cord, and this leads to poor bladder control, impotence, etc. We are mimicking this problem experimentally by damaging the spinal nerves that carry these signals. We have found that after this type of damage the pelvic ....This project is about the effects of spinal injury on autonomic neurons that control the bladder, lower bowel and reproductive organs. One of the consequences of some types of spinal injury is that there are no signals being sent from the spinal cord to the nerve cells outside the cord, and this leads to poor bladder control, impotence, etc. We are mimicking this problem experimentally by damaging the spinal nerves that carry these signals. We have found that after this type of damage the pelvic autonomic neurons make many new connections between each other, and the types of new connections depend on which spinal nerves have been injured. This leads to the question: are these new connections good or bad? ie are they helpful in trying to get organ control back to normal or will they stop the correct connections from the spinal cord from being made in the future? This project addresses these questions by using sophisticated techniques for staining and visualising individual nerve fibres growing out from the spinal cord. We will track how well these fibres grow back and connect with the pelvic autonomic neurons. In particular, we will see whether they make correct connections, and if these connections are influenced by the new fibres that have grown between the autonomic neurons in the interim period. We will also do physiological tests to see if the new connections have the correct function. The ultimate aim of these studies is not only to understand more about regeneration, but to see what determines whether the correct connections have been made - and ideally, to give us insight into how we can make regeneration work more quickly and accurately. We believe that this work is an important adjunct to other studies on spinal injury, which mostly focuses on regaining voluntary motor control (e.g. walking); however loss of bladder, bowel and reproductive function is another important quality of life issue for spinal injury patients.Read moreRead less
Characterisation Of Ion Channels That Are Potential Therapeutic Targets In Enteric Neurons
Funder
National Health and Medical Research Council
Funding Amount
$535,141.00
Summary
Disorders of intestinal movement (motility) are common and cause considerable suffering, absenteeism and social disruption. Disorders include motility disturbances that occur in irritable bowel syndrome (IBS); constipation, which is a considerable problem in the aged; slow transit disorders; and diarrhoea. The movements of the intestine are controlled by the enteric nervous system. This project aims to find targets for therapy of motility disorders within the enteric nervous system
Determination Of Sympathetic Preganglionic Neuronal Phenotype
Funder
National Health and Medical Research Council
Funding Amount
$241,527.00
Summary
The nervous system is the single most complex part of our body. Its function depends on millions of connections between neurons, all of which must form correctly during development. Furthermore, each neuron must select a neurotransmitter with which to talk to its target neuron. A neurotransmitter is a chemical released from a neuron, which passes a signal to a target cell. Some neurotransmitters cause excitation of the target cell, others inhibition. Each neurotransmitter signals to the target c ....The nervous system is the single most complex part of our body. Its function depends on millions of connections between neurons, all of which must form correctly during development. Furthermore, each neuron must select a neurotransmitter with which to talk to its target neuron. A neurotransmitter is a chemical released from a neuron, which passes a signal to a target cell. Some neurotransmitters cause excitation of the target cell, others inhibition. Each neurotransmitter signals to the target cell via receptor molecule, matched to the neurotransmitter. Thus, a neuron is faced not only with making choices about what connections to make within the developing brain, but also it must select from a range of potential neurotransmitters and receptor molecules. We are interested in how neurons select the appropriate neurotransmitter. There are a number of ways that a neuron might be guided to the correct choice. It is possible that it could receive from the target cell a signal that guides the choice of neurotransmitter. We wish to examine this hypothesis to see if it is applicable to the autonomic nervous system, that part of the nervous system that controls functions like changes in blood pressure and heart rate. Our laboratory is expert in identifying the chemistry of autonomic neurons. We will use this knowledge to see what happens when we deliberately perturb the normal connections of autonomic neurons. Do they persist in expressing the neurotransmitters they would have done prior to the perturbation? Alternatively, do they adapt to the change of target via a signal received from the new target cell and express the appropriate phenotype? The results of these experiments will give insights into how the brain develops. The results will be important for both our basic understanding of biology and as a basis for the development of techniques for reversing neuronal damage.Read moreRead less
Distribution, Pharmacology, Molecular Identity And Roles Of Purine Receptors In Enteric Neurons
Funder
National Health and Medical Research Council
Funding Amount
$395,250.00
Summary
Digestive function needs to be adapted to the great variety of foods that we eat, and to our variable dietary habits. Adaptation is controlled through an extensive nervous system in the wall of the gastrointestinal tract, the enteric nervous system, and through digestive system hormones. The enteric nervous system detects the volume and key chemical components in the gastrointestinal lumen and, through an integrating nerve circuitry, causes changes in the patterns of movement, fluid secretion an ....Digestive function needs to be adapted to the great variety of foods that we eat, and to our variable dietary habits. Adaptation is controlled through an extensive nervous system in the wall of the gastrointestinal tract, the enteric nervous system, and through digestive system hormones. The enteric nervous system detects the volume and key chemical components in the gastrointestinal lumen and, through an integrating nerve circuitry, causes changes in the patterns of movement, fluid secretion and local blood flow. Digestive system diseases, for example irritable bowel syndrome, can involve disordered function of the enteric nervous system, and there is considerable research and development focus to identify drug targets in the enteric nervous system that can be used in therapy. Amongst potential targets are receptors for purines that are located on enteric neurons and are one of the important classes of receptor that is involved in communication between the neurons. These studies aim to identify the purine receptors, their roles in controlling digestive function and their potential as therapeutic targets in the treatment of digestive disease.Read moreRead less
Mechanisms Of Testosterone Action On The Male Pelvic Autonomic Nervous System: The Role Of Estrogens
Funder
National Health and Medical Research Council
Funding Amount
$417,750.00
Summary
The aim of this project is to understand how the circulating hormone, testosterone, affects the autonomic nervous system in adult males. We are particularly interested in the effects this hormone has on the nerve supply of the urogenital organs, ie. the lower urinary tract and reproductive organs. We have already found that many different parts of this pelvic autonomic nervous system are androgen-sensitive, and if the levels of hormones drop significantly, then many properties of the neurons cha ....The aim of this project is to understand how the circulating hormone, testosterone, affects the autonomic nervous system in adult males. We are particularly interested in the effects this hormone has on the nerve supply of the urogenital organs, ie. the lower urinary tract and reproductive organs. We have already found that many different parts of this pelvic autonomic nervous system are androgen-sensitive, and if the levels of hormones drop significantly, then many properties of the neurons change. This is likely to impact negatively on reflexes like penile erection, prostate secretion and propulsion of seminal fluid. Our recent experiments suggest that many of these actions may be caused by testosterone acting in a way that does not involve the typical activation of its receptor molecule (the androgen receptor) and we think it is very likely that it is first converted by some pelvic autonomic neurons into estradiol. We have recently shown that estradiol has potent actions on signalling cascades in these neurons, and that many of the neurons make estrogen receptors. It is also possible that testosterone causes the release of growth factors from the organs, and these growth factors cause changes in their nerve supply. We will investigate both of these possibilities. The outcomes of this study will be relevant for understanding how pelvic autonomic reflexes are affected by endocrine disorders, ageing and various drugs that act on the endocrine system. Our results may also be useful for designing drugs that act on the endocrine system but with less side-effects on the nervous system.Read moreRead less
Cardiac Sympathetic Nerve Activity: Understanding Normal Control And The Causes Of The Increase In Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$531,125.00
Summary
Heart failure is a condition in which the heart muscle becomes weak and is unable to pump sufficient blood around the body to provide adequate perfusion of the organs. This results in breathlessness, lethargy, fatigue, mental confusion and eventually death. At present the life expectancy of patients with heart failure is poor, with a 5 year survival of 25% in men and 38% in women. It is the only form of heart disease that is increasing, the reason being that thousands of patients who have surviv ....Heart failure is a condition in which the heart muscle becomes weak and is unable to pump sufficient blood around the body to provide adequate perfusion of the organs. This results in breathlessness, lethargy, fatigue, mental confusion and eventually death. At present the life expectancy of patients with heart failure is poor, with a 5 year survival of 25% in men and 38% in women. It is the only form of heart disease that is increasing, the reason being that thousands of patients who have survived heart attacks or had coronary bypass operations go on to develop heart failure. In heart failure there is a very large increase in the activity of the nerves that stimulate cardiac rate and contractility, the cardiac sympathetic nerves. This increase in activity is detrimental, higher levels of activity predict greater morbidity and a reduced life span. The mechanisms causing the increase in cardiac sympathetic nerve activity are unknown, but greater understanding is essential if new and improved treatments are to be developed for patients with heart failure. Only two groups in the world measure cardiac nerve activity in conscious animals, neither is studying heart failure. We therefore have a unique opportunity to investigate the factors that control the activity of the cardiac nerves in the healthy state and to establish the causes of the increase in activity in heart failure. In particular, we will investigate how reflex control mechanisms, circulating hormones that are increased in heart failure and specific mechanisms in the brain act to control cardiac nerve activity in the normal state and what changes in these mechanisms lead to the preferential increase in cardiac nerve activity in heart failure. These findings will provide a detailed understanding of the mechanisms controlling cardiac nerve activity in the normal healthy state and increased knowledge of the factors that lead to the preferential activation of the cardiac nerves in heart failure.Read moreRead less
Modulation Of Autonomic Nerve Growth By Guidance Factors
Funder
National Health and Medical Research Council
Funding Amount
$393,277.00
Summary
Our goal is to understand how adult nerves are affected by injury so that we can devise therapies to make them regrow better. We will focus on nerves that control the urogenital organs because these are often injured during surgical procedures (e.g. prostatectomy, hysterectomy), with devastating effects on patients' quality of life. In this project we will investigate how naturally-occurring growth-inhibitory molecules affect nerve regrowth after injury in the pelvic nervous system.
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
Very little is known about mechanisms whereby depression harms the heart. This is especially disturbing as recent evidence indicates that while antidepressants alleviate a depressed persons negative mood, they do not eliminate danger to the heart. We will use an animal model to determine: How depression affects the electrical stability of the heart; The identity of the brain mechanisms that are involved; and which drugs can be used to protect the heart fro the harmful effects of depression.