Understanding The Role Of Infectious Agents As A Trigger Of Crohns Disease In Children With Early Onset Disease
Funder
National Health and Medical Research Council
Funding Amount
$570,876.00
Summary
Crohn's disease is a major cause of illness throughout the world. There is no cure and current therapies carry substantial risks. An infectious agent has been suggested as the trigger for disease but research has been inconclusive. Our study focuses on the characterisation of a novel virus we have identified that may trigger Crohn's disease in children at disease onset.
Neural Coordination Of Intestinal Motility And Mucosal Secretion Of Water And Salt - Role In Toxin Induced Diarrhoea
Funder
National Health and Medical Research Council
Funding Amount
$490,020.00
Summary
This project deals with some of the basic mechanisms underlying disorders of gastrointestinal function and in particular with the mechanisms responsible for diarrhoea. Whenever there is a natural disaster (the recent tsunami for example) or a war, the breakdown of medical services leads to concern about outbreaks of cholera and other diarrhoea causing diseases, so understanding the mechanisms by which the cholera bacterium cause diarrhoea remains a major imperative. It is known that the diarrhoe ....This project deals with some of the basic mechanisms underlying disorders of gastrointestinal function and in particular with the mechanisms responsible for diarrhoea. Whenever there is a natural disaster (the recent tsunami for example) or a war, the breakdown of medical services leads to concern about outbreaks of cholera and other diarrhoea causing diseases, so understanding the mechanisms by which the cholera bacterium cause diarrhoea remains a major imperative. It is known that the diarrhoea resulting from cholera infection is produced by an enterotoxin, which acts to produce a massive over-secretion of water and salt through the intestinal wall, which if it is not controlled causes death by dehydration. This effect requires the activity of the nerve cells within the gut wall, the enteric nervous system (ENS). Other bacterial toxins have similar effects and also require activity of the ENS for these effects to be manifested. This project will identify how these toxins alter the activity of the ENS and the effects that they have on intestinal movements which are also regulated by the ENS. We already know that the movements and secretion of water are related to each other and that this relationship is disturbed in some more subtle diseases like irritable bowel syndrome. This project will characterise this relationship, thereby shedding light on the physiology underlying a variety of gastrointestinal 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 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.
Effects Of Intestinal Inflammation On Functioning Of Enteric Neurons: From Animal Models To Humans
Funder
National Health and Medical Research Council
Funding Amount
$345,206.00
Summary
Crohn’s disease and ulcerative colitis, two debilitating conditions known as Inflammatory Bowel Disease (IBD), affect more than 61,000 Australians. There is no cure for IBD. All gut functions are controlled by enteric neurons in the gut wall. Inflammation causes damage and death of these neurons leading to gut dysfunctions. This is the first study defining the classes of human enteric neurons affected by inflammation. This study will test several potential new targets for the treatment of IBD.
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.
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
Faecal Microbiota Transplantation And Other Novel Therapeutic Microbial Manipulation Strategies In Inflammatory Bowel Disease
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
There is growing interest in the role of microbial-based strategies including faecal microbiota transplantation (FMT) for the treatment of inflammatory bowel disease. This project will develop such strategies into valid treatment options through a combination of clinical & basic science work including (1) characterising viral & fungal factors of importance, (2) evaluation of novel orally-delivered formulations of FMT, and (3) development of better defined, more reproducible microbial treatments.