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 Transferrin Receptor, Divalent Metal Transporter, Ferroportin And Hemochromatosis Protein In Iron Absorption
Funder
National Health and Medical Research Council
Funding Amount
$195,990.00
Summary
Within Australia 1 in 300 people of Caucasian origin have a genetic defect which makes them absorb more iron from the diet than they need. Excess iron is a major problem because it damages cells and this is most obvious in the pancreas where the cells make insulin are destroyed and diabetes mellitus develop. In the liver cirrhosis and cancer often occur. Iron also accumulates in other tissues such as the heart and joints resulting in damage to these organs. The genetic defect has recently been i ....Within Australia 1 in 300 people of Caucasian origin have a genetic defect which makes them absorb more iron from the diet than they need. Excess iron is a major problem because it damages cells and this is most obvious in the pancreas where the cells make insulin are destroyed and diabetes mellitus develop. In the liver cirrhosis and cancer often occur. Iron also accumulates in other tissues such as the heart and joints resulting in damage to these organs. The genetic defect has recently been identified but how the defective protein causes the cells of the intestine to absorb more iron into the body than is needed remains unknown. This has led to the idea that the normal protein is responsible for controlling the amount of iron absorbed. Recent studies have shown a link between this protein and another called transferrin receptor. These two molecules are thought to co-operate in determining how much iron will be absorbed. Once this is determined other molecules called iron transporters are produced and these are responsible for moving the iron from the intestine into the blood. When not much iron is required only a small number of transporters are made and when more iron is required then many more are produced. How these transporters program the level of iron absorption is unknown but the process probably involves the transferrin receptor and the hemochromatosis protein. This project will investigate the function of the molecules that determine the programe for how much iron is to be absorbed, and secondly how this is linked to the production and movement of the transproters that co-ordinate this function.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.
How Spinal Afferent Nerves Cause Vasodilation Of Mesenteric Arteries
Funder
National Health and Medical Research Council
Funding Amount
$353,250.00
Summary
Healthy function of the gastrointestinal tract requires an adequate blood supply during periods of varying demand. Inadequate blood supply to the gut contributes to disorders ranging in severity from mild through to lethal. Reduced blood supply to the gut is a trigger for multiple organ failure syndrome; a leading cause of death in critically ill patients following major surgery, trauma or haemorrhage. It is believed that damage to the lining of the gut, during periods of reduced flow, trigger i ....Healthy function of the gastrointestinal tract requires an adequate blood supply during periods of varying demand. Inadequate blood supply to the gut contributes to disorders ranging in severity from mild through to lethal. Reduced blood supply to the gut is a trigger for multiple organ failure syndrome; a leading cause of death in critically ill patients following major surgery, trauma or haemorrhage. It is believed that damage to the lining of the gut, during periods of reduced flow, trigger inflammatory mechanisms throughout the body. Mesenteric ischaemia is a disorder which occurs as a chronic, non-occlusive form, or as acute episodes, which are often lethal, . Temporary increases in blood supply are also known to play a vital role in protecting the gut from acid, toxins and attack by pathogens. The major mechanism underlying increases in bloody supply is dilation of arterial vessels. This occurs focally, at the site of damage, via local mechanisms, but this is supplemented by a more widespread dilation of arteries upstream, mediated by branches of sensory neurones that innervate blood vessels directly. Currently, there is no information about how these sensory neurones are activated. This is crucial to understand how they work. We hypothesise that these sensory neurones are activated by chemical and mechanical stimuli in the gut wall, which make them release vasodilator chemicals onto the arteries upstream and thus amplify the local increases in blood flow. We will test this by recording from sensory nerves, identifying the ones which project to blood vessels and determine which chemicals and mechanical stimuli they are excited by. We will then fill them with dye, using a method that we have recently developed, to visualise their branching patterns both inside and outside the gut wall. In this way, we will understand how this powerful protective mechanism is activated at times of need, and how it may fail under some circumstances.Read moreRead less
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.
Novel Applications Of Ghrelin Peptides In Mouse Models Of Inflammatory Bowel Disease
Funder
National Health and Medical Research Council
Funding Amount
$243,116.00
Summary
Inflammatory bowel disease (IBD) is a debilitating, chronic condition that often affects patients in the primes of their lives. A limited number of treatments are currently available for these patients and those that are available often have serious side effects, including growth restriction in children. Ghrelin is a natural hormone that has been shown to suppress many features of IBD. This project will investigate the potential of ghrelin as a new treatment for inflammatory bowel disease.
Factors Controlling Leucocyte Migration In Healthy Intestine And In Inflammatory Bowel Disease
Funder
National Health and Medical Research Council
Funding Amount
$195,217.00
Summary
Inflammatory bowel diseases (IBD) are relapsing and remitting disorders of the intestine that create substantial disability in a relatively young population of patients. Our treatments for these conditions have changed little in the last 30 years and they are commonly accompanied by side effects. Research into the mechanisms controlling the gut inflammation offers promise for the development of novel, targeted and less toxic therapies. The major mediators of damage in IBD are white blood cells r ....Inflammatory bowel diseases (IBD) are relapsing and remitting disorders of the intestine that create substantial disability in a relatively young population of patients. Our treatments for these conditions have changed little in the last 30 years and they are commonly accompanied by side effects. Research into the mechanisms controlling the gut inflammation offers promise for the development of novel, targeted and less toxic therapies. The major mediators of damage in IBD are white blood cells recruited from the circulation to affected intestine. This recruitment is induced by the production in damaged intestine of chemokines, proteins of the immune system that attract and activate white blood cells. Chemokines act through chemokine receptors on the surface of white blood cells, and earlier research by our group has demonstrated that these chemokine receptors can be functionally modulated by neuropeptides, proteins unrelated to chemokines that normally transmit messages within the nervous system. This project aims to explore the chemokines and chemokine receptors responsible for the recruitment of white blood cells to normal and IBD-affected intestine, in order to determine therapeutic targets for novel treatments. Moreover, the role of neuropeptides in modulating the recruitment of white blood cells to the intestine will be examined in cells from the human intestine, both normal and IBD-affected, as well as in an animal model of IBD. This project will provide an understanding of the signals responsible for the attraction of damaging white blood cells to sites of inflammation in the bowel and will indicate mechanisms used by the immune system to regulate those signals. It has the potential to direct us to new therapies that use highly targeted and physiologically appropriate approaches to controlling white blood cell trafficking in health and disease.Read moreRead less
Functional Relationships Of Gastrin And Its Regulators In The Developing And Diseased Gastrointestinal Tracts
Funder
National Health and Medical Research Council
Funding Amount
$607,832.00
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 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 c ....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 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. The production and effects of gastrin are mediated in part by the local factor histamine and modified by the hormone somatostatin. The amount, type and activity of gastrin, and the interactions with histamine and somatostatin, will be measured in foetal and newborn animals, and people with or at risk of developing colon cancer.Read moreRead less
Intestinal Adaptation Following Massive Small Intestinal Resection: Mechanisms And Management
Funder
National Health and Medical Research Council
Funding Amount
$256,980.00
Summary
Short bowel syndrome (SBS) remains a major clinical problem in paediatric and adult clinical practice. The Department of Gastroenterology and Clinical Nutrition at the Royal Children's Hospital has gained recognition as a national centre of excellence for the management of infants and children with SBS and intestinal failure. Due to the significant personal and heath-care burden related to SBS there has been an urgent need to improve understanding about the process of intestinal adaptation follo ....Short bowel syndrome (SBS) remains a major clinical problem in paediatric and adult clinical practice. The Department of Gastroenterology and Clinical Nutrition at the Royal Children's Hospital has gained recognition as a national centre of excellence for the management of infants and children with SBS and intestinal failure. Due to the significant personal and heath-care burden related to SBS there has been an urgent need to improve understanding about the process of intestinal adaptation following massive small bowel resection (MSBR) in order to develop new treatments aimed at improving clinical outcome for patients with SBS. Over the past 5 years we have developed a preclinical model for the study of intestinal adaptation in infants using the juvenile pig. Our recent studies in this model have revealed that elemental formula is inferior to whole protein formula suggesting that the current clinical recommendations need urgent re-evaluation. Using the preclinical model in this proposal, we aim to define the mechanisms underlying the adaptive response and evaluate novel therapies aimed at enhancing adaptation following MSBR. Supplementation of enteral feeds with bovine colostrum isolate resulted in normal growth in the preclinical model despite MSBR. In this proposal we plan to advance this observation for the first time to human clinical trials in infants with SBS. Even small gains in enteral tolerance during the early post-operative period may have a significant impact on morbidity and mortality of children with SBS due to parenteral-nutrition related liver disease and gut-related sepsis. This research proposal provides a unique link between studies aimed at providing the scientific basis for understanding the mechanisms of intestinal adaptation using an established preclinical model and translating the results of these studies onto human trials, taking advantage of the clinical expertise available in the management of children with SBS.Read moreRead less