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
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
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.
Mechanisms Regulating Nutrient Induced Motor Patterns In The Isolated Small Intestine
Funder
National Health and Medical Research Council
Funding Amount
$427,750.00
Summary
The movements of the small intestine are essential for the digestion and absorption of a meal and consist of two basic patterns during a 3-4 hour period after a meal. These are mixing (or segmentation) and propulsion (or peristalsis). Although it is the subject of ongoing study, much is known about the basic mechanisms that control propulsion, largely because this behaviour is readily seen in isolated segments of gut so it is possible to undertake highly controlled experiments to identify the va ....The movements of the small intestine are essential for the digestion and absorption of a meal and consist of two basic patterns during a 3-4 hour period after a meal. These are mixing (or segmentation) and propulsion (or peristalsis). Although it is the subject of ongoing study, much is known about the basic mechanisms that control propulsion, largely because this behaviour is readily seen in isolated segments of gut so it is possible to undertake highly controlled experiments to identify the various cellular components of the system. By contrast, mixing has only been reliably seen in intact animals making studies of the detailed mechanisms responsible for this behaviour much more difficult. What is known is that the composition of a meal controls the relative amount of mixing and propulsion seen at any location along the small intestine. We have recently identified a pattern of contractions in isolated small intestine (duodenum and-or jejunum) that is induced by the presence of a nutrient in the intestine and appears very similar to the mixing behaviour seen in the intact animal. We have shown that this pattern depends on the activity of nerve cells including those that excite the gut muscle and that it depends on the activity of a hormone released from the lining of the gut wall by fats and other nutrients. The aims of this proposal are to identify how nutrients interact to produce this pattern of contractions, the relative roles of specific types of nerve cells and the sites at which the local hormones released by nutrients act. This is important because increasing the proportion of mixing to propulsion enhances the absorption of nutrient from a meal, so if the mechanisms that initiate mixing behaviour can be regulated in a predictable way by specific nutrient, absorption can be enhanced in various malabsorption syndromes.Read moreRead less
The Role Of Prostaglandins In The Control Of Intestinal Motility In Physiological And Experimental Inflammatory States.
Funder
National Health and Medical Research Council
Funding Amount
$316,209.00
Summary
Many intestinal disorders are due to inflammations of unknown origin, associated with pain, diarrhoea or constipation. How this occurs is not known. The movements of the intestine are due to the contractions and relaxations of the muscular wall, which are controlled by a network of nerve cells, a kind of a brain in the gut. In inflammatory conditions, a multitude of chemical substances are produced by the sick gut. Among these substances are the prostaglandins that are responsible for increasing ....Many intestinal disorders are due to inflammations of unknown origin, associated with pain, diarrhoea or constipation. How this occurs is not known. The movements of the intestine are due to the contractions and relaxations of the muscular wall, which are controlled by a network of nerve cells, a kind of a brain in the gut. In inflammatory conditions, a multitude of chemical substances are produced by the sick gut. Among these substances are the prostaglandins that are responsible for increasing pain from inflamed parts. However, the gut makes prostaglandins even when there is no inflammation, although it is not clear what do these substances do in the normal intestine. During disease, prostaglandins are made in much larger amounts. If we can establish what they do normally we may be able to establish how they work in disease. Therefore our projects is in two parts. First, we will investigate how prostaglandins normally affect the working of the nerves and muscle controlling intestinal movement. In the second part we will reveal the role of these substances during mild inflammation induced in some laboratory animals to mimic human diseases. All experiments will be carried out on intestines removed from these experimental animals after they are killed humanely. This enables us to study how the experimentally induced diseases affect gut function, especially movement. We will use a method, that has recently been developed in our laboratory, to transform video recordings of gut movements into computer-generated maps. From these pictures, we can see patterns of movement that are too subtle to detect by just watching the videos. We will end our project by establishing if and when prostaglandins are responsible for producing the abnormal intestinal movements seen in disease. This will give clinicians a better basis to develop new drugs against gut disorders.Read moreRead less
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