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
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
Our objective is to understand the biological significance of the interaction between iron and the hormone gastrin. The project's significance to human health lies in the fact that gastrins stimulate growth of the lining of the stomach and colon, accelerate the development of gastrointestinal cancers, and may be involved in iron homeostasis. Recognition that iron is essential for the biological activity of gastrins may allow the development of novel therapies for colon cancer and iron overload.
Exclusive Enteral Nutrition In Children With Crohns Disease
Funder
National Health and Medical Research Council
Funding Amount
$364,549.00
Summary
Crohn's disease occurs at any age, even in young children. One treatment for CD involves the use of a special drink (nutritional treatment). This works well for CD in children, helping to settle symptoms and heal the bowel surface. Despite being established as a treatment for 20 years, it is not yet clear how it works. These studies aim to work out how nutritional treatments work in CD. This should expand our knowledge about CD and may lead to further ways to prevent or manage CD.
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
Trafficking Of Receptors And Receptor Associated Proteins In Enteric Neurons And Their Effectors
Funder
National Health and Medical Research Council
Funding Amount
$178,910.00
Summary
Movement of food through the alimentary tract and digestion of that food are controlled by the enteric nervous system which is embedded in the walls of the stomach and intestines. The neurons of the enteric nervous system contain and release chemicals that act as neurotransmitters, passing messages from one neuron to the next. Abnormalities of neuronal function can result in increased sensitivity (pain) from the gut, contents moving in reverse (reflux), or failure to move contents (stasis) resul ....Movement of food through the alimentary tract and digestion of that food are controlled by the enteric nervous system which is embedded in the walls of the stomach and intestines. The neurons of the enteric nervous system contain and release chemicals that act as neurotransmitters, passing messages from one neuron to the next. Abnormalities of neuronal function can result in increased sensitivity (pain) from the gut, contents moving in reverse (reflux), or failure to move contents (stasis) resulting in maldigestion. Many of the chemicals involved in transmission between neurons have been identified. An important further question is: where, in a pathway consisting of many neurons, is each chemical released and where does it have its effect? We are using techniques to see the chemicals within the neurons using fluorescent tags, confocal microscopy and computer imaging. We are also able to see the molecules that the transmitters bind to (their receptors) and to see changes in these receptors that occur when the chemical messenger binds. We can look at the neurons within the intestine and determine the individual neurons that receive a particular chemical message. We are determining the location of neurons that are activated by acetylcholine (the major transmitter causing excitation of neurons and contraction of the muscle), tachykinins (peptides involved in pathways of contraction, relaxation and pain) and other transmitters (vasoactive intestinal peptide, somatostatin, gastrin releasing peptide, cholecystokinin and motilin) involved in contraction, relaxation and secretion. The results of this study will provide a rational basis for therapeutic treatment of disorders that involve changes in the normal release of neurotransmitters or changes in the activation of their receptors.Read moreRead less
Progastrin Derived Peptides: Biological Activities And Functions In The Gastrointestinal Tract
Funder
National Health and Medical Research Council
Funding Amount
$454,500.00
Summary
Gastrin is a hormone from the stomach which aids digestion by stimulating acid secretion. However too much acid can cause ulcers of the gastrointestinal tract. Gastrin also stimulates the growth of the lining of the stomach and intestines. This growth promoting effect is important for the development of the gastrointestinal tract before birth and may also be involved in a number of cancers especially colon cancer. Several different forms of gastrin are made by endocrine cells of the stomach and ....Gastrin is a hormone from the stomach which aids digestion by stimulating acid secretion. However too much acid can cause ulcers of the gastrointestinal tract. Gastrin also stimulates the growth of the lining of the stomach and intestines. This growth promoting effect is important for the development of the gastrointestinal tract before birth and may also be involved in a number of cancers especially colon cancer. Several different forms of gastrin are made by endocrine cells of the stomach and by cancers of the colon. It seems that the different types of gastrins have different effects and act through distinct receptors, but we do not know which are the most important forms and whether all forms are biologically active. The amount, type and activity of the different gastrins, and the regions of the molecule that are essential for biological activity, will be investigated using cell lines, animal models that overproduce too much gastrin, animal models of colon cancer and in patients with colon cancer. Colorectal carcinoma (cancer of the large bowel) is the second most common cause of cancer death. A successful outcome will result in the development of assays for the early diagnosis and monitoring of bowel cancer and the potential for novel treatments such as gastrin receptor antagonists and radiolabelled gastrin analogues for radiotherapy.Read moreRead less
Migration And Differentiation Of Enteric Neuron Precursors
Funder
National Health and Medical Research Council
Funding Amount
$385,116.00
Summary
There are many millions of nerve cells within the wall of the intestine, and they control many intestinal functions, including motility. During development, these nerve cells arise from cells which migrate away from the developing brain and first enter the stomach. The migratory cells are called neural crest cells. After entering the stomach, neural crest cells migrate within the wall of the gastrointestinal tract, until they reach the far (anal) end. In embryonic mice, this colonisation of the ....There are many millions of nerve cells within the wall of the intestine, and they control many intestinal functions, including motility. During development, these nerve cells arise from cells which migrate away from the developing brain and first enter the stomach. The migratory cells are called neural crest cells. After entering the stomach, neural crest cells migrate within the wall of the gastrointestinal tract, until they reach the far (anal) end. In embryonic mice, this colonisation of the entire small and large intestines by neural crest cells takes over 4 days, and in humans the process probably takes at least one week. It is essential that the neural crest cells colonise the entire gastrointestinal tract, since regions of intestine lacking neural crest cells (and hence nerve cells) cannot function and intestinal contents build up in front of the region lacking nerve cells. This condition is found in some babies (Hirschsprung's disease), and it can only be treated by surgically removing the region lacking nerve cells. It is therefore essential that migratory neural crest cells colonise the entire gastrointestinal tract. Currently, little is known about the mechanisms controlling the migration of neural crest cells, and whether a) particular molecules within the gut wall are important for migration, and-or b) the migratory behaviour of the neural crest cells is regulated mostly by the neural crest cells themselves. In this study we will take time-lapse images of neural crest cells migrating through the gut of embryonic mice to identify the factors that are important for the migration. After the neural crest cells have colonised the entire intestine, they develop into different types of nerve cells. We will also examine some of the factors affecting the development of different types of nerve cells.Read moreRead less
Gastrokine 2: A Novel Stomach-specific Tumour Suppressor Gene
Funder
National Health and Medical Research Council
Funding Amount
$342,735.00
Summary
We will evaluate how a natural protein called gastrokine 2 acts to prevent cancer from developing in the stomach. We will show how gastrokine 2 interacts with another stomach protein TFF1, to block the effects of the inflammatory and cancer causing bacterium Helicobacter pylori, and the way that this bacterium circumvents this by turning off the production of gastrokine 2. Finally a drug which inhibits stomach tumour growth by turning on gastrokine 2 will be tested.