The Mechanisms Through Which Opiates Cause Gastrointestinal Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$410,594.00
Summary
Opiates are the mainstay analgesics for severe pain. However, their use in pain relief can be greatly limited due to gut-related side-effects. These include chronic constipation, which is mediated through actions on neurons in the intestine. In this proposal we will examine the role of key proteins, known as beta arrestins, in the generation of opiate-induced constipation. Knowledge derived from this study will facilitate the development of analgesics with fewer gastrointestinal side-effects.
Shigella Flexneri O Antigen Polysaccharides: Biosynthesis, Function In Virulence, And Interaction With IcsA/VirG
Funder
National Health and Medical Research Council
Funding Amount
$468,055.00
Summary
Shigella flexneri bacteria cause dysentery in millions of humans each year. The bacterium invades and replicates within the cells of the large intestine. Inside cells, S. flexneri is able to use the host cell's actin-based motility machinery to become motile within the cells, and this can be seen as F-actin comet tails extending from one end of the cell. Bacterial cell surface components residing in the outer membrane are important for the bacterium's ability to cause disease. Two of these compo ....Shigella flexneri bacteria cause dysentery in millions of humans each year. The bacterium invades and replicates within the cells of the large intestine. Inside cells, S. flexneri is able to use the host cell's actin-based motility machinery to become motile within the cells, and this can be seen as F-actin comet tails extending from one end of the cell. Bacterial cell surface components residing in the outer membrane are important for the bacterium's ability to cause disease. Two of these components (lipopolysaccharides (LPS) and their polysaccharide chains (O antigens), and IcsA-VirG protein)) are required for initiating actin polymerisation, and mutations affecting synthesis of these components reduce ability to cause disease. In previous studies we have found that O antigen and the synthesis and function of IcsA are interrelated. This project will study how the O antigens are synthesised and their chain length determined by the Wzz protein, and the Wzz structure in relation to its function will also be characterised. The role played by O antigen in intracellular motility will be studied to determine the mechanisms involved. Infection of cells and cell free extracts, antibodies, and an enzyme which specifically degrades the O antigen, will be used to study how O antigen affect the interaction between bacteria with human cell proteins. The relationship between O antigen and IcsA function will be studied using monoclonal antibodies raised to IcsA. The effect of LPS on the outer membrane protease IcsP will be investigated, as will the effect of LPS lipid A mutations on O antigen and virulence. These studies will contribute to a better understanding of the biosynthesis of an ubiquitous bacterial cell surface component (O antigen), its function as a virulence factor in bacterial interactions with host cells. This may lead to novel therapeutic strategies to prevent and control Shigellosis and other bacterial infections.Read moreRead less
TRANSCUTANEOUS ELECTRICAL STIMULATION TO TREAT CONSTIPATION DUE TO ANORECTAL RETENTION IN CHILDREN
Funder
National Health and Medical Research Council
Funding Amount
$635,320.00
Summary
If you don't poop, you die! Over 20% of older people have constipation. It starts in childhood in 1/100 people and lasts through life. At the Royal Children’s Hospital, Melbourne, we have been developing a physiotherapy method using electrical stimulation across the skin to treat long-term constipation. In this study we are comparing this treatment to current treatment in the most common type of chronic constipation in children.
Development Of The GUTSTIM Device For The Treatment Of Intractable Constipation
Funder
National Health and Medical Research Council
Funding Amount
$380,746.00
Summary
We have developed a new treatment for chronic constipation that uses electrical stimulation through the skin similar to physiotherapy treatments for sports injuries. 20 million people (3% of children and 20% of the elderly) have chronic constipation. This proposal is to develop a simple purpose-built machine that has the best electronic properties for stimulating the intestine. The machine will be simple, easy to use and cheap, allowing safe use at home by children and the elderly.
Over 80 million people have chronic constipation. It affects over 1/5 older people and is a major problem in aged-care. We have found that a painless method of electrical stimulation across the abdomen can overcome chronic constipation in children and adults. We will test the method to see what types of constipation it can help, including constipation caused by pain-medication and irritable bowel syndrome. This treatment is given at home and could improve life for many people around the world.
Translational Studies Of Novel Methods For The Assessment Of Gastrointestinal Motility.
Funder
National Health and Medical Research Council
Funding Amount
$713,517.00
Summary
Swallowing has complex physiology and swallowing problems (dysphagia) result in poor nutrition and death due to complications of aspiration. A/Prof Omari has invented a new method to assess swallowing function. The studies proposed will change how dysphagia is diagnosed and managed. The research follows three streams: (A) studies in large patient cohorts in whom a better diagnosis is needed (e.g. stroke), (B) studies of therapies and interventions and (C) studies of swallowing biomechanics.
How Intestinal Motility Activates Sensory Pathways
Funder
National Health and Medical Research Council
Funding Amount
$555,875.00
Summary
Pain and discomfort from the gut are common and unpleasant. We understand how gut sensory nerve cells work, at the cellular, molecular and genetic level. However, movement of the gut wall and contents are the major cause of activation of sensory neurons. We know little about which particular patterns of movement cause pain. This is crucial information for accurately diagnosing human gut disorders, for monitoring effectiveness of treatments and for identifying potential new drug targets.
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.
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