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
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.
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
Effects Of Intestinal Inflammation On Functioning Of Enteric Neurons: From Animal Models To Humans
Funder
National Health and Medical Research Council
Funding Amount
$345,206.00
Summary
Crohn’s disease and ulcerative colitis, two debilitating conditions known as Inflammatory Bowel Disease (IBD), affect more than 61,000 Australians. There is no cure for IBD. All gut functions are controlled by enteric neurons in the gut wall. Inflammation causes damage and death of these neurons leading to gut dysfunctions. This is the first study defining the classes of human enteric neurons affected by inflammation. This study will test several potential new targets for the treatment of IBD.
Neural Coordination Of Intestinal Motility And Mucosal Secretion Of Water And Salt - Role In Toxin Induced Diarrhoea
Funder
National Health and Medical Research Council
Funding Amount
$490,020.00
Summary
This project deals with some of the basic mechanisms underlying disorders of gastrointestinal function and in particular with the mechanisms responsible for diarrhoea. Whenever there is a natural disaster (the recent tsunami for example) or a war, the breakdown of medical services leads to concern about outbreaks of cholera and other diarrhoea causing diseases, so understanding the mechanisms by which the cholera bacterium cause diarrhoea remains a major imperative. It is known that the diarrhoe ....This project deals with some of the basic mechanisms underlying disorders of gastrointestinal function and in particular with the mechanisms responsible for diarrhoea. Whenever there is a natural disaster (the recent tsunami for example) or a war, the breakdown of medical services leads to concern about outbreaks of cholera and other diarrhoea causing diseases, so understanding the mechanisms by which the cholera bacterium cause diarrhoea remains a major imperative. It is known that the diarrhoea resulting from cholera infection is produced by an enterotoxin, which acts to produce a massive over-secretion of water and salt through the intestinal wall, which if it is not controlled causes death by dehydration. This effect requires the activity of the nerve cells within the gut wall, the enteric nervous system (ENS). Other bacterial toxins have similar effects and also require activity of the ENS for these effects to be manifested. This project will identify how these toxins alter the activity of the ENS and the effects that they have on intestinal movements which are also regulated by the ENS. We already know that the movements and secretion of water are related to each other and that this relationship is disturbed in some more subtle diseases like irritable bowel syndrome. This project will characterise this relationship, thereby shedding light on the physiology underlying a variety of gastrointestinal disorders.Read moreRead less
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.
Neural Control Of Colorectal Function And Identification Of Sites Of Drug Action
Funder
National Health and Medical Research Council
Funding Amount
$375,489.00
Summary
Constipation is a considerable problem, especially in the elderly; it occurs in 20-25% of people over 65 and in about 50% of people in nursing homes. It is also a significant concern for children, with up to 30% being affected. There are no adequate treatments and the majority of people are dissatisfied with their management. We have discovered a class of compounds that stimulate defecation. In this project we will test the effectiveness of these compounds to relieve constipation.