Neurotransmission In Functionally Distinct Vasodilator Pathways
Funder
National Health and Medical Research Council
Funding Amount
$809,934.00
Summary
A surprising feature of our body is that there is not enough blood to fully supply all our organs at once. This is why we sometimes faint when we are hot or get cramps when we are exercising. Consequently, the blood vessels change their diameter so that blood can be directed to the organs with greatest demand at any particular time. For example, if the vessel decreases in diameter, less blood flows through it, but if it increases in diameter, more blood flows through it to reach the appropriate ....A surprising feature of our body is that there is not enough blood to fully supply all our organs at once. This is why we sometimes faint when we are hot or get cramps when we are exercising. Consequently, the blood vessels change their diameter so that blood can be directed to the organs with greatest demand at any particular time. For example, if the vessel decreases in diameter, less blood flows through it, but if it increases in diameter, more blood flows through it to reach the appropriate organ. An important function of the nervous system is to control the flow of blood to different organs by changing the diameters of the blood vessels. One set of nerves decreases the diameter of the arteries, and another set of nerves increases the diameter. The nerves do this by releasing special combinations of chemicals when they get a message from the brain to do so. In this project we are especially interested in the nerves which increase blood flow to organs in the head and the pelvis. We will use a wide range of modern methods to find out how these nerves work. In some experiments, we will use sophisticated electrical equipment to measure just how the nerve cells controlling the diameter of the vessels respond to the instructions sent by the brain. In other experiments, we will find out which chemicals the nerves use to make the blood vessels increase in diameter. We also will discover how the various chemicals get released by the nerves at the right times, so that messages from the brain get to the blood vessels as efficiently as possible. One of the special parts of our project is that we will be able to observe directly the connections between the nerve cells and the blood vessels we are studying. Our results will be important for designing new drugs that could help people whose nerves are not working properly, such as in some patients with diabetes or vascular disease.Read moreRead less
Gastrointestinal Sensory Function In Normal And Diseased States
Funder
National Health and Medical Research Council
Funding Amount
$691,026.00
Summary
Chronic pain and discomfort from the digestive system is a major health care issue world-wide. There is currently no effective treatment for these problems, which often have no apparent organic cause. Lack of treatment is due to a lack of understanding about how sensations are transmitted from the digestive system to the brain. Our research group has unique and powerful techniques that allow us to probe the basic mechanisms of sensory function, and make rapid progress towards finding drugs that ....Chronic pain and discomfort from the digestive system is a major health care issue world-wide. There is currently no effective treatment for these problems, which often have no apparent organic cause. Lack of treatment is due to a lack of understanding about how sensations are transmitted from the digestive system to the brain. Our research group has unique and powerful techniques that allow us to probe the basic mechanisms of sensory function, and make rapid progress towards finding drugs that reduce specific types of sensory signals from the gut. We shall investigate sensory mechanisms in the upper and lower regions of the gut, where symptoms are most prevalent in diseases such as non-cardiac chest pain, functional dyspepsia and irritable bowel syndrome. Six aspects of sensory nerve endings in the gut are to be investigated: 1. The grouping of endings into functional classes (similar to touch or pressure receptors in skin) 2. How endings respond to chemicals and hormones found in the gut 3. How currently available drugs may be useful in reducing sensitivity 4. The mechanisms by which inflammation affects sensitivity 5. How nerve growth factors may trigger changes in sensitivity 6. How pores or channels in nerve endings determine their functionRead moreRead less
Integrative Properites Of Intrinsic Sensory Neurons Of The Intestine
Funder
National Health and Medical Research Council
Funding Amount
$211,681.00
Summary
For the neuronal control of the intestine to be appropriate to the constantly changing state of the organ, it is essential that there is feedback concerning, amongst other things, distension by its contents and its contractile state. These properties of the intestine are monitored by intrinsic sensory neurons, which are very special sensory cells, because they are embedded in the wall of the organ that they control. They have only very recently been identified, and thus surprisingly little is kn ....For the neuronal control of the intestine to be appropriate to the constantly changing state of the organ, it is essential that there is feedback concerning, amongst other things, distension by its contents and its contractile state. These properties of the intestine are monitored by intrinsic sensory neurons, which are very special sensory cells, because they are embedded in the wall of the organ that they control. They have only very recently been identified, and thus surprisingly little is known about how they perform their functions. It is clear, however, that they have special ways of integrating information about their environment, and the activities of other neurons, that are not shared by any other sensory neurons identified to the present time. Thus investigation of these neurons will provide information that is almost completely lacking about how the intestine performs its tasks. This information will be valuable in defining targets for development of therapeutic compounds and in analysing disorders of intestinal motility.Read moreRead less
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
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.
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