The Role Of Voltage-gated Na+ And Ca2+ Channels In Post-inflammatory Hyperexcitability Of Enteric Neurons
Funder
National Health and Medical Research Council
Funding Amount
$520,000.00
Summary
Gastrointestinal inflammation causes changes in neurons that control gut functions (motility and secretion). These changes in neuronal properties lead to the development of post-inflammatory motility disorders. This will be the first detailed study of neuronal ion channels that are changed after inflammation in the gut. Our study will open the way to the development of therapeutic agents to treat post-inflammatory IBS and other conditions that involve disorders of motility.
Long Term Changes In Excitability Of Enteric Neurons
Funder
National Health and Medical Research Council
Funding Amount
$198,414.00
Summary
A large proportion of the community, about 20% at any one time, suffer from functional bowel disorders, the most common of which is the irritable bowel syndrome (IBS). The bowel in these patients appears normal; there are no overt changes in its appearance. However, the patients have discomfort, pain, abdominal bloating and altered bowel habits, which can include constipation and-or diarrhoea. There is general agreement that an alteration in the responsiveness of sensory neurons of the digestive ....A large proportion of the community, about 20% at any one time, suffer from functional bowel disorders, the most common of which is the irritable bowel syndrome (IBS). The bowel in these patients appears normal; there are no overt changes in its appearance. However, the patients have discomfort, pain, abdominal bloating and altered bowel habits, which can include constipation and-or diarrhoea. There is general agreement that an alteration in the responsiveness of sensory neurons of the digestive tract occurs in IBS. Until our recent discovery of long-term increases in excitability of intrinsic sensory neurons in the small intestine, no possible cellular basis for altered sensory neuron responsiveness that could underlie IBS had been found. We will investigate the mechanism of the long-term increase in excitability and will investigate drugs that are expected to modify its induction and-or maintenance. We expect that this work will aid in unravelling the genesis of IBS and will eventually lead to strategies to treat this common debilitating condition.Read moreRead less
Participation Of Intrinsic Sensory Neurons In The Initiation Of Colonic And Gastric Reflexes
Funder
National Health and Medical Research Council
Funding Amount
$109,448.00
Summary
The gastrointestinal tract adjusts its digestive activity in response to the food that we eat. To do this, the bulk and chemical composition of the food and products of digestion must be sensed. In the small intestine, this sensing is by neurons in the wall on the intestine (intrinsic neurons) and by neurons with cells outside the intestine and endings in its wall (extrinsic neurons). There is evidence for there being intrinsic sensory neurons in the colon, subserving fewer functions than in the ....The gastrointestinal tract adjusts its digestive activity in response to the food that we eat. To do this, the bulk and chemical composition of the food and products of digestion must be sensed. In the small intestine, this sensing is by neurons in the wall on the intestine (intrinsic neurons) and by neurons with cells outside the intestine and endings in its wall (extrinsic neurons). There is evidence for there being intrinsic sensory neurons in the colon, subserving fewer functions than in the small intestine, but direct recordings from putative colonic intrinsic sensory neurons during sensory stimuli have not been made. The literature does not indicate whether there are intrinsic sensory neurons in the stomach. Some data suggests they may be present only in the antrum. It is important to determine whether there are intrinsic sensory neurons in the colon and stomach, which seems likely, to identify them morphologically and physiologically, and to investigate their responsiveness to physiological sensory stimuli. These data may be useful to understand the pathogenesis of functional bowel disorders, including delayed emptying in the stomach (which occurs in diabetes, for example) and slow transit constipation. Proper identification and characterisation of intrinsic sensory neurons might guide the development of therapies for disorders of colonic and gastric motility.Read moreRead less
Trafficking Of Receptors And Receptor Associated Proteins In Enteric Neurons And Their Effectors
Funder
National Health and Medical Research Council
Funding Amount
$178,910.00
Summary
Movement of food through the alimentary tract and digestion of that food are controlled by the enteric nervous system which is embedded in the walls of the stomach and intestines. The neurons of the enteric nervous system contain and release chemicals that act as neurotransmitters, passing messages from one neuron to the next. Abnormalities of neuronal function can result in increased sensitivity (pain) from the gut, contents moving in reverse (reflux), or failure to move contents (stasis) resul ....Movement of food through the alimentary tract and digestion of that food are controlled by the enteric nervous system which is embedded in the walls of the stomach and intestines. The neurons of the enteric nervous system contain and release chemicals that act as neurotransmitters, passing messages from one neuron to the next. Abnormalities of neuronal function can result in increased sensitivity (pain) from the gut, contents moving in reverse (reflux), or failure to move contents (stasis) resulting in maldigestion. Many of the chemicals involved in transmission between neurons have been identified. An important further question is: where, in a pathway consisting of many neurons, is each chemical released and where does it have its effect? We are using techniques to see the chemicals within the neurons using fluorescent tags, confocal microscopy and computer imaging. We are also able to see the molecules that the transmitters bind to (their receptors) and to see changes in these receptors that occur when the chemical messenger binds. We can look at the neurons within the intestine and determine the individual neurons that receive a particular chemical message. We are determining the location of neurons that are activated by acetylcholine (the major transmitter causing excitation of neurons and contraction of the muscle), tachykinins (peptides involved in pathways of contraction, relaxation and pain) and other transmitters (vasoactive intestinal peptide, somatostatin, gastrin releasing peptide, cholecystokinin and motilin) involved in contraction, relaxation and secretion. The results of this study will provide a rational basis for therapeutic treatment of disorders that involve changes in the normal release of neurotransmitters or changes in the activation of their receptors.Read moreRead less
Mechanisms Of Long Term Excitability Changes In Enteric Neurons
Funder
National Health and Medical Research Council
Funding Amount
$308,250.00
Summary
The intestine contains within its walls a nerve circuitry, the enteric nervous system, that controls many of its activities. The intestine itself adapts to circumstances, such as diet, and to pathological changes, such as infection or inflammation. In fact, changes in the intestine can outlast the events that cause them. This implies that there are prolonged changes in properties of control systems in the intestine. We have discovered that the intrinsic sensory neurons of the intestine exhibit l ....The intestine contains within its walls a nerve circuitry, the enteric nervous system, that controls many of its activities. The intestine itself adapts to circumstances, such as diet, and to pathological changes, such as infection or inflammation. In fact, changes in the intestine can outlast the events that cause them. This implies that there are prolonged changes in properties of control systems in the intestine. We have discovered that the intrinsic sensory neurons of the intestine exhibit long-term excitability increases following prolonged, low frequency, stimulation of their inputs from other neurons. This phenomenon has been called sustained slow postsynaptic excitation (SSPE). We have begun to examine the mechanisms behind the SSPE, and have discovered that it involves the enzymatic modification of molecules in the intrinsic sensory neurons. In this work, we will identify the enzymes and their molecular targets. This will add to basic knowledge of how the digestive system performs its task and adapts over time. It will provide data that can be used to predict molecules that might be of therapeutic value in dealing with chronic disorders in the intestine, such as irritable bowel syndrome.Read moreRead less
Migration And Differentiation Of Enteric Neuron Precursors
Funder
National Health and Medical Research Council
Funding Amount
$385,116.00
Summary
There are many millions of nerve cells within the wall of the intestine, and they control many intestinal functions, including motility. During development, these nerve cells arise from cells which migrate away from the developing brain and first enter the stomach. The migratory cells are called neural crest cells. After entering the stomach, neural crest cells migrate within the wall of the gastrointestinal tract, until they reach the far (anal) end. In embryonic mice, this colonisation of the ....There are many millions of nerve cells within the wall of the intestine, and they control many intestinal functions, including motility. During development, these nerve cells arise from cells which migrate away from the developing brain and first enter the stomach. The migratory cells are called neural crest cells. After entering the stomach, neural crest cells migrate within the wall of the gastrointestinal tract, until they reach the far (anal) end. In embryonic mice, this colonisation of the entire small and large intestines by neural crest cells takes over 4 days, and in humans the process probably takes at least one week. It is essential that the neural crest cells colonise the entire gastrointestinal tract, since regions of intestine lacking neural crest cells (and hence nerve cells) cannot function and intestinal contents build up in front of the region lacking nerve cells. This condition is found in some babies (Hirschsprung's disease), and it can only be treated by surgically removing the region lacking nerve cells. It is therefore essential that migratory neural crest cells colonise the entire gastrointestinal tract. Currently, little is known about the mechanisms controlling the migration of neural crest cells, and whether a) particular molecules within the gut wall are important for migration, and-or b) the migratory behaviour of the neural crest cells is regulated mostly by the neural crest cells themselves. In this study we will take time-lapse images of neural crest cells migrating through the gut of embryonic mice to identify the factors that are important for the migration. After the neural crest cells have colonised the entire intestine, they develop into different types of nerve cells. We will also examine some of the factors affecting the development of different types of nerve cells.Read moreRead less
Neural Mechanisms Mediating Hypersecretion And Motility Patterns Induced By Enterotoxins
Funder
National Health and Medical Research Council
Funding Amount
$415,250.00
Summary
This project aims to identify the nerve cells that are responsible for the massive oversecretion of water and salt seen with cholera and other diseases producing diarrhoea. Many of these disease act through specific toxins and, although the biochemical targets of these toxins are reasonably well understood, the nerve cells on which they act have never been identified. Furthermore, the mechanisms that couple the oversecretion with a massive increase in the propulsive activity of the intestine are ....This project aims to identify the nerve cells that are responsible for the massive oversecretion of water and salt seen with cholera and other diseases producing diarrhoea. Many of these disease act through specific toxins and, although the biochemical targets of these toxins are reasonably well understood, the nerve cells on which they act have never been identified. Furthermore, the mechanisms that couple the oversecretion with a massive increase in the propulsive activity of the intestine are also unknown. We will investigate each of these questions using the small intestine of the guinea-pig, because the nerve circuit in this preparation is better understood than that of any other. Nerve cells that respond to three specific toxins, each known to activate the nervous system via different mechanisms, will be determined using intracellular recording methods, injection of marker dyes and methods that allow the identification of their neurochemistry. This will allow the functions of responsive nerve cells to be identified and their places in the circuits that control secretion and propulsion to be determined. This information will be correlated with studies in whole animals being undertaken in Sweden so that potential sites for intervention can be identified.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
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