Evolution And Function Of A Novel Lateral Flagellar Locus, Flag-2, In Pathogenic Escherichia Coli
Funder
National Health and Medical Research Council
Funding Amount
$465,158.00
Summary
This project will study how the bacteria that cause infant diarrhoea colonize the intestine and induce disease. We have identified a novel genetic region that allows E. coli to survive and persist in the intestine. Similar genes are also present in closely related organisms. This project will help us to undestand how new diseases evolve and emerge and may lead to the development of new vaccines to protect against infant diarrhoea.
Contribution Of Nuclear Targeting Of The NleE-OspZ Family Of Proteins To Escherichia Coli And Shigella Virulence
Funder
National Health and Medical Research Council
Funding Amount
$542,462.00
Summary
This project will study how the bacteria that cause infant diarrhoea colonize the intestine and induce disease. We have identified new bacterial proteins that allow E. coli to manipulate the normal host cell processes involved in killing an invading bacterium. Similar proteins are also present in the closely related organism, Shigella which causes dysentary. We will determine how these proteins act by finding the host cell proteins they bind.
Novel Probiotics And Naturally-sourced Extracts As Treatment Strategies For Chemotherapy-induced
Funder
National Health and Medical Research Council
Funding Amount
$322,183.00
Summary
Intestinal mucositis is a serious disorder associated with chemotherapy treatment in cancer patients. Recently, a new strain of probiotic bacteria has been described with the potential to decrease the severity of intestinal mucositis. However, it is not known whether the live probiotic is necessary for this effect. We will compare the live probiotic, dead probiotic and factors sourced from this probiotic for the potential to decrease the severity of intestinal mucositis. Similarly, there have be ....Intestinal mucositis is a serious disorder associated with chemotherapy treatment in cancer patients. Recently, a new strain of probiotic bacteria has been described with the potential to decrease the severity of intestinal mucositis. However, it is not known whether the live probiotic is necessary for this effect. We will compare the live probiotic, dead probiotic and factors sourced from this probiotic for the potential to decrease the severity of intestinal mucositis. Similarly, there have been anecdotal claims of medicinal application for so-called ‘bioactive’ extracts and formulations derived from a range of mammalian, marine and plant sources. Specifically, Lyprinol (an extract derived from the New Zealand Green-Lipped Mussel), Emu Oil (derived from Emu meat) and the herbal extract Iberogast, have been reported to possess antiinflammatory properties. Indeed, these agents are used widely for the adjunctive relief of symptoms associated with arthritis and joint pain. However, these agents have yet to be tested for their potential to treat or prevent intestinal mucositis. For the first time, utilizing proven, controlled animal model systems, the current submission will explore the therapeutic potential of these agents, alone and in combination with indicated probiotics, for their capacity to treat or prevent mucositis. Should efficacy be demonstrated, a potential mechanism of action will be sought by investigating effects on intestinal stem cells.Read moreRead less
The Role Of SPARC In Intestinal Extracellular Matrix Changes And Carcinogenesis
Funder
National Health and Medical Research Council
Funding Amount
$526,728.00
Summary
The inflammatory bowel diseases (IBDs), Crohn s disease (CD) and ulcerative colitis (UC), are lifelong, chronic, incurable conditions and the number of patients being diagnosed with these conditions is increasing worldwide. Over recent years there has been the development of new treatments effective in controlling the chronic inflammation of the bowel in many of these patients. There is no evidence, however that these therapies reduce the rate of bowel scarring or the development of bowel cancer ....The inflammatory bowel diseases (IBDs), Crohn s disease (CD) and ulcerative colitis (UC), are lifelong, chronic, incurable conditions and the number of patients being diagnosed with these conditions is increasing worldwide. Over recent years there has been the development of new treatments effective in controlling the chronic inflammation of the bowel in many of these patients. There is no evidence, however that these therapies reduce the rate of bowel scarring or the development of bowel cancer that complicated these conditions. Healing of the bowel inflammation can result in scarring. Whether scarring develops or not hinges on the balance between tissue production and destruction. If production outstrips destruction then scarring may occur, but if this balance can be modified in favour of reduced production then, potentially, healing may proceed without scarring. This project aims to investigate the role of a protein, SPARC, that can regulate scar formation and its interactions with other proteins that can alter scar formation in a mouse model of chronic bowel inflammation. Chronic inflammation of the bowel can also cause the development of colon cancer. Colon cancer is one of the most common cancers in the Australian population. The level of SPARC in the colon cancer at time of initial surgery may predict the risk of disease recurrence. The aim of this study is to determine if SPARC levels can identify those patients at higher risk of cancer recurrence. The role of SPARC will also be examined in a mouse model of colon cancer to determine if increased SPARC levels increased or decrease the rate of cancer growth and its spread.Read moreRead less
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
The Effects Of Intestinal Inflammation On The Currents And Channels Of Identified Enteric Neurons
Funder
National Health and Medical Research Council
Funding Amount
$476,264.00
Summary
Intestinal inflammation, in gastroenteritis, Crohn's disease, ileitis or colitis, has effects on the motility (movement) of the gastrointestinal and on secretion within it. The symptoms that are recognised are poor digestion, crampy pains and diarrhoea. The symptoms often continue after the inflammation has subsided. The major disease entity that can develop after inflammation is the irritable bowel syndrome (IBS). IBS is associated with persistent disorders of bowel motility. The symptoms are t ....Intestinal inflammation, in gastroenteritis, Crohn's disease, ileitis or colitis, has effects on the motility (movement) of the gastrointestinal and on secretion within it. The symptoms that are recognised are poor digestion, crampy pains and diarrhoea. The symptoms often continue after the inflammation has subsided. The major disease entity that can develop after inflammation is the irritable bowel syndrome (IBS). IBS is associated with persistent disorders of bowel motility. The symptoms are triggered by changes in the properties of enteric neurons, many of which become hyperexcitable. Enteric neurons are part of the nervous system within the gut wall. However, the neurons that have changed properties after inflammation have not been identified, and the mechanisms of change are not known. This work is designed to determine the molecular basis of the changes in neuron excitability that lead to hyperexcitability. Identification of the molecules whose properties are changed will permit those molecules to be targeted in the design of compounds to treat the abnormalities of intestinal physiology that follow inflammation.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.
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