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
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
Role Of Calcium Channels And Small-conductance Potassium Channels In Myenteric Neurons
Funder
National Health and Medical Research Council
Funding Amount
$131,717.00
Summary
This proposal will investigate the electrical properties of neurons in the wall of the intestine that control movements of the bowel. These neurons form an extensive network that runs the length of the gastrointestinal tract and control mixing and propulsion of food along the intestine. We will determine the basic electrical properties of these neurons and investigate why some of them transmit signals in a continuous manner while others transmit signals intermittently and how these patterns of a ....This proposal will investigate the electrical properties of neurons in the wall of the intestine that control movements of the bowel. These neurons form an extensive network that runs the length of the gastrointestinal tract and control mixing and propulsion of food along the intestine. We will determine the basic electrical properties of these neurons and investigate why some of them transmit signals in a continuous manner while others transmit signals intermittently and how these patterns of activity fit into the overall activity of the gut. This study will build on a large body of data obtained from our laboratory that has shown that some of these neurons act as sensors of the presence-absence of food in the intestine while others send signals to the muscle in the wall of the intestine to either relax or contract it so that the food can be processed properly. By knowing what makes these neurons different from each other we will be able to understand what goes wrong in functional bowel disorders where motility is affected, resulting in pain and discomfort.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
How The Intestinal Microenvironment Controls Propulsion And Mixing Of Food In The Gut: Parallel Transduction Pathways
Funder
National Health and Medical Research Council
Funding Amount
$1,157,350.00
Summary
This project will identify the mechanisms that control the mixing of food with digestive juices, the absoprtion of nutrients from the gut to the blood stream and the excretion of waste. Disruption of these processes causes significant health problems and is associated with normal aging and many diseases. We will identify nutrients and other food components (eg spices) that switch gut from mixing to propulsion and hence identify targets to treat disorders of gut movement.
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
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.
Properties And Electro-Physiology Of The Intrinsic Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$419,214.00
Summary
The gut contains a very large number of nerve cells which fall into several functionally distinct groups. We have identified virtually all these functional groups in the guinea-pig small intestine and have begun an analysis of the ways the different groups communicate with each other. We have developed methods to identify the functions of any nerve cell from which we record and have also developed novel methods for specifically stimulating individual functional classes of nerve cells that contac ....The gut contains a very large number of nerve cells which fall into several functionally distinct groups. We have identified virtually all these functional groups in the guinea-pig small intestine and have begun an analysis of the ways the different groups communicate with each other. We have developed methods to identify the functions of any nerve cell from which we record and have also developed novel methods for specifically stimulating individual functional classes of nerve cells that contact them. The aim of the proposed research is to exploit these methods to identify the chemicals used by specifc types of nerve cell in transmission of information to other nerve cells during the normal behaviour of the intestine. We will record the behaviour of individual nerve cells in the gut wall while stimulating specific nerve pathways that contact them. We will then use drugs that block the activity of the chemicals of interest (small proteins called tachykinins, and certain amine compounds) to try and block the transmission of information between the nerve cells involved. Identification of the nature of the chemicals used at specific connections between different functional groups of nerve cells in the gut will allow the design of drugs for treatment of gastrointestinal disorders that will have minimal side effects. Further because the chemicals that are used for communication in the gut are also found in the brain, the results will provide evidence about the functions of these chemicals elsewhere in the nervous system.Read moreRead less
The applicant aims to improve treatment of digestive disease by identifying and understanding the interactions between the nervous system and the gastrointestinal (GI) tract, with emphasis on sensory systems.
Mechanosensitive Afferent Nerves And Gastrointestinal Motility
Funder
National Health and Medical Research Council
Funding Amount
$384,693.00
Summary
This project aims to identify the different types of sensory nerves from the gut which cause sensations such as fullness, nausea or pain. These sensory nerves also activate important reflexes that coordinate different regions of the gut to ensure that food is properly digested and propelled. Many studies have examined these sensory nerves and how they can be activated by stretching the gut wall, but very basic questions remain to be answered. We do not know how many different types of sensory ne ....This project aims to identify the different types of sensory nerves from the gut which cause sensations such as fullness, nausea or pain. These sensory nerves also activate important reflexes that coordinate different regions of the gut to ensure that food is properly digested and propelled. Many studies have examined these sensory nerves and how they can be activated by stretching the gut wall, but very basic questions remain to be answered. We do not know how many different types of sensory nerves there are and whether they all respond to stretch in the same way. We cannot identify their specialised endings in the wall of the gut. While these sensory nerves definitely respond to stretch, they are also known to respond to contractions of the gut wall. Despite this, we do not understand how the normal movements of the gut wall activate them, nor why some movements can lead to pain. Most of the experiments will be carried out on small pieces of tissue taken from humanely killed guinea pigs and studied, under highly controlled conditions, in organ baths. The remainder of the study will be on specimens of human gut tissue obtained at surgery. This project will use new techniques to record sensory nerves during both stretch and contraction of the gut wall to understand what activates them. In addition, their endings will be labelled with dye to reveal their different shapes. Using computerised imaging techniques we will identify whether they respond to particular patterns of movement in the gut wall. Lastly we will record from these sensory neurones in live specimens of human colon to see whether the same types of sensory nerves are present in humans as in the small animals. This study will provide the first comprehensive account of sensory nerves to the gut wall that respond to distension, including those that activate pain pathways. This is a pre-requisite for designing new drugs that will target these nerve cells with minimal side effects.Read moreRead less