The intestinal lining is continuously renewed by specialised cells called intestinal stem cells. Stem cells throughout the body are regulated by nearby connective tissues. But, the identity of these supportive cells in the gut are unknown. We test whether a discrete population of connective tissue cells in the gut support intestinal stem cells. This project will identify new cellular therapies and targets to promote intestinal repair and manage intestinal cancer.
Bioresponsive Porous Silicon For Site Specific Oral Delivery Of Antibodies For The Treatment Of Inflammatory Bowel Disease
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
This proposal aims to develop an oral antibody delivery system for treatment of inflammatory bowel disease (IBD) that affects 75000 Australians. The system will be based on porous silicon nanoparticles acting as a container to protect the antibodies, and bioresponsive coatings acting as gates to enable site specific protein delivery at the inflamed site of GI tract. The project not only holds promise for protein delivery for the treatment of IBD but other diseases like diabetes.
Neurogenic Diarrhoea: Lessons From Cholera Toxin And Related Bacterial Exotoxins
Funder
National Health and Medical Research Council
Funding Amount
$543,818.00
Summary
Many bacteria that cause diarrhoea act via the gut’s own nervous system to massively increase the transport of water and salt into the lumen of the intestine. In this project we will investigate mechanisms that lead to this over-excitation of the gut’s nervous system to test the idea that this is due to a change in the properties of the final nerve cells in the normal pathway that controls water transport. This will identify novel sites for drug treatments of diarrhoea.
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
Building An Intestine: Manipulating Regeneration Of The Epithelium
Funder
National Health and Medical Research Council
Funding Amount
$609,424.00
Summary
Diseases, infections and pathologies are common clinical problems of the intestinal lining in both infants and adults. Individuals with these conditions can experience nutritional problems and severe cases result in death. The intestinal lining is generated from a small population of stem cells. In this study we use of a mouse model where the stem cells are marked and will examine what factors regulate stem cells in the intestine with the aim of facilitating intestinal tissue regeneration.
Cancer is linked to mutations in a large variety of genes but how these changes impact on cell behaviour is often unknown. We are using functional genomics in zebrafish to identify genes that are essential for rapid rates of proliferation by intestinal epithelial cells. Seven genes have been cloned so far and our next task is to analyse, using mouse models and human cancer transcriptome analysis, whether any are indispensable for cancer growth and thereby present suitable targets for therapy.
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