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.
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
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
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
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
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.
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
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
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 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