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
Currents That Set The Excitability Of Enteric Neurons And Their Roles At Cell And Organ Levels
Funder
National Health and Medical Research Council
Funding Amount
$459,014.00
Summary
The intestine is subject to a number of disorders of its normal control by nerves, including diarrhoea, constipation and slow transit disorders. Chronic and debilitating derangement of intestinal function occurs in irritable bowel syndrome, which affects around 10-15% of people in our community, about 1% at any one time. Irritable bowel syndrome can persist for many years, and there is no adequate therapy. For some patients no medication gives relief, and for most the relief is minimal. The refl ....The intestine is subject to a number of disorders of its normal control by nerves, including diarrhoea, constipation and slow transit disorders. Chronic and debilitating derangement of intestinal function occurs in irritable bowel syndrome, which affects around 10-15% of people in our community, about 1% at any one time. Irritable bowel syndrome can persist for many years, and there is no adequate therapy. For some patients no medication gives relief, and for most the relief is minimal. The reflexes in the intestine that control its movements and secretion depend for their initiation on a special type of neuron, known as the intrinsic primary afferent neuron. These neurons have properties that determine how active they are. These properties distinguish them from all other enteric neurons. If the activity of intrinsic primary afferent neurons is controlled, then the intensity and character of enteric reflexes are also controlled. Thus it is feasible to target molecules in these neurons that could be used to treat constipation or diarrhoea, or to accelerate movement of food along the intestine. Our work has identified molecular targets and some of the medicinal compounds that could be useful to patients. The project will further define the molecular targets, determine the specificity of potential treatments and test the effectiveness of the medicinal compounds in an animal model.Read moreRead less
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
ATP Release From Gastrointestinal Epithelium: A Potential Target For The Treatment Of Slow Transient Constipation
Funder
National Health and Medical Research Council
Funding Amount
$317,775.00
Summary
Slow transit constipation (STC) is a severe condition of the colon, almost exclusively affecting reproductive age women with no effective treatment. We recently found an association between STC and defects in connexin proteins in the large intestine. We aim to reveal the role of connexins and female hormones in the maintenance of normal intestinal function and their involvement in STC. The study will provide completely new perspectives in the understanding of the functional bowel disorders.
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.
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
Migratory Behaviour And Cell Cycle Length Of Enteric Neuron Precursors
Funder
National Health and Medical Research Council
Funding Amount
$472,249.00
Summary
The activity of nerves in the intestine is essential for gastrointestinal function. Correct development of intestinal neurons requires migration of precursors to the correct location and control of proliferation to achieve correct neuron number. In this project we will identify the mechanisms regulating migration and proliferation of intestinal neuron precursors during normal development, and in mice with defects in intestinal neurons that are models of human motility disorders.
Prof Kamm is a gastroenterologist interested in developing improved treatments for gastrointestinal and pelvic floor disorders, such as inflammatory bowel disease and functional disorders. He runs basic science, translational and clinical strands of research in parallel across the same areas of interest, developing new treatments that encompass physiological, pharmacological, surgical and psychological therapies.