Spatio-temporal Analysis Of Rat Intestinal Motility In Physiological And Disease Models
Funder
National Health and Medical Research Council
Funding Amount
$358,750.00
Summary
This project addresses the question of how the movements of the gut are controlled in health and disease. The progress of food along the gut is due to movements of the involuntary muscle of the wall of the intestine. Three fundamental mechanisms are involved. One is the spontaneous ability of the intestinal muscle to contract rhythmically and is driven by a delicate net of pacemaker cells. Fast propulsion of food contents depends on nerve circuits in the gut wall that generate a powerful pumping ....This project addresses the question of how the movements of the gut are controlled in health and disease. The progress of food along the gut is due to movements of the involuntary muscle of the wall of the intestine. Three fundamental mechanisms are involved. One is the spontaneous ability of the intestinal muscle to contract rhythmically and is driven by a delicate net of pacemaker cells. Fast propulsion of food contents depends on nerve circuits in the gut wall that generate a powerful pumping behaviour to prevent over-filling or to eject toxic or irritating substances (eg: some laxatives activate this mechanisms). This is often called peristalsis. A third mechanism consists of activity of nerve cells in the gut, that slowly propagates along the intestine and causes the muscle to contract, sweeping along any remnants. The movements generated by these three mechanisms occur in segments of intestine isolated from rats. The major difficulty up until now has been to relate the actual movements in living animals to these fundamental mechanisms. It is now possible to bridge this gap because we have developed methods to record, display and measure graphically the actual movements. Movements are transformed into spatio-temporal maps which show all of the contractions over a period of time. Coordinated activity is visible in these maps as recognisable patterns or visual objects. Measurements can be readily made with conventional statistics. The literature in gastroenterology is full of descriptions of motility based on indirect methods of recordings. In this project we will be able to correlate the previous indirect methods with the new graphic methods and thus establish a clearer, simpler and more accurate classification of normal patterns of intestinal motility. We will then use this to establish what goes wrong in a number of experimental diseases known to affect adversely the movements of the intestine.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
The Neural Control Of Serotonin Release From Intestinal Enterochromaffin (EC) Cells
Funder
National Health and Medical Research Council
Funding Amount
$117,187.00
Summary
Many functional gastrointestinal problems are believed to be caused by a disruption of the normal functioning of the nerves within the wall of the gut. These nerves are believed to receive information about the contents of the intestine from a specialised class of cell lining the inside wall of the gut called the enterochromaffin cell. The enterochromaffin cell does this job by modulating the release of the transmitter serotonin. In some disorders, like the Irritable Bowel Syndrome (IBS) which c ....Many functional gastrointestinal problems are believed to be caused by a disruption of the normal functioning of the nerves within the wall of the gut. These nerves are believed to receive information about the contents of the intestine from a specialised class of cell lining the inside wall of the gut called the enterochromaffin cell. The enterochromaffin cell does this job by modulating the release of the transmitter serotonin. In some disorders, like the Irritable Bowel Syndrome (IBS) which can affect the upper and lower intestine, the information that serotonin carries can become confused. Thus, the control of the release of serotonin from the enteroendocrine cell is an important process to understand in health and in disease. We will investigate this release directly in isolated tissues from guinea pig small and large intestine and from human large intestine. This study will examine the role of serotonin and the modulation of its release from the enterochromaffin cell. Problems with serotonin release may underlie disease, thus, understanding how this release is controlled will provide a foundation for new and specific therapies that target channels or receptors specific to the release of serotonin. These data could help to develop therapies for gastrointestinal problems such as the IBS, chronic intestinal pseudo-obstruction and gastro-oesophageal reflux disease. The release of serotonin is also intimately linked with the diarrhea associated with cholera and anti-cancer treatments. The proposed study will contribute to the ongoing development of specific therapies that block serotonin receptors on the nerve terminal and will lead to new therapies that compliment existing therapies by modulating the release of serotonin.Read moreRead less
The Knotty Problem Of Enterochromaffin Cells And Gastro-intestinal Function: Unravelling Cause And Effect
Funder
National Health and Medical Research Council
Funding Amount
$403,097.00
Summary
It is crucial to understand how the food we eat controls the secretions and movements of a healthy or a diseased gastrointestinal (GI) system. One way control is achieved involves the release of serotonin (5-HT) from the enterochromaffin cells present in the epithelial lining of the intestine. This is the subject of our proposal and our results will help us to understand the causes of GI disorders and help to formulate new treatments.
Characterisation Of The Anti-inflammatory Properties Of The N-3 Fatty Acid Product, 4-hydroxy-hexenal.
Funder
National Health and Medical Research Council
Funding Amount
$524,559.00
Summary
A concerted effort is being made by experts in the field of omega 3 fats (fish oils) to make specific recommendation on their use to improve human health . We have reasoned that the characterisation of a major oxidation product of these oils could be a key to understanding how these fats benefit us. The project is likely to influence the formulation of fish oils to enhance their health promoting properties.
Mechanisms By Which Aging Induces Constipation In The Elderly
Funder
National Health and Medical Research Council
Funding Amount
$369,717.00
Summary
Chronic constipation is one of the most common reasons why the elderly community seek medical attention. There is now strong evidence to suggest that the high prevalence of constipation in the elderly is likely due to a dramatic loss of specific nerves that lie in the wall of the colon. This project will use latest imaging technologies to identify the mechanisms by which these nerves are impaired with age that lead to constipation in the elderly.
Defining The Role Of Tumour Necrosis Factor Apoptosis Inducing Ligand (TRAIL) In Experimental Visceral Leishmaniasis.
Funder
National Health and Medical Research Council
Funding Amount
$153,250.00
Summary
The activation of pathogen-specific T cells by dendritic cells (DC) is a critical step in the control of most infections, as well as the success of many vaccine strategies. The specific cells and molecules involved in this process are still poorly defined. In this project, we will investigate the effects of a cell surface molecule called tumour necrosis factor related apoptosis inducing ligand (TRAIL) on the ability of DC to activate T cells during a parasitic infection caused by Leishmania dono ....The activation of pathogen-specific T cells by dendritic cells (DC) is a critical step in the control of most infections, as well as the success of many vaccine strategies. The specific cells and molecules involved in this process are still poorly defined. In this project, we will investigate the effects of a cell surface molecule called tumour necrosis factor related apoptosis inducing ligand (TRAIL) on the ability of DC to activate T cells during a parasitic infection caused by Leishmania donovani. By identifying the cells that express TRAIL and the effect that this molecule has on the development of immunity to pathogens, we will better understand the factors required to generate effective immune responses against infectious agents, and hence, develop better vaccines.Read moreRead less
Effects Of Ischemia/ Reperfusion Injury On Enteric Neurons And Neuroprotective Strategies
Funder
National Health and Medical Research Council
Funding Amount
$566,277.00
Summary
The intestine can suffer restricted blood flow, creating a region of damaged or dead bowel. This leads to severe medical emergencies, complications and even death. Loss of blood flow and damage can be a serious complication for intestinal transplant surgery, which compromises patient survival and recovery. The project brings together transplant surgeons and basic scientists to solve problems caused by intestinal ischemia. A major result will be to improve outcomes for Australian patients