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 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
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.
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
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.
Neural Circuits Producing Pelvic Vasodilation In Females
Funder
National Health and Medical Research Council
Funding Amount
$472,770.00
Summary
The reproductive organs and genitalia in males and females experience a large increase in blood flow during sexual and reproductive activity. This increased blood flow (vasodilation) is a key component of penile and clitoral erection, and enhances secretion from the lining of the internal reproductive organs. Vasodilation during sexual activity is produced by a special sets of nerves receiving signals from the genitalia and the brain. In fact, Viagra works by enhancing and prolonging the actions ....The reproductive organs and genitalia in males and females experience a large increase in blood flow during sexual and reproductive activity. This increased blood flow (vasodilation) is a key component of penile and clitoral erection, and enhances secretion from the lining of the internal reproductive organs. Vasodilation during sexual activity is produced by a special sets of nerves receiving signals from the genitalia and the brain. In fact, Viagra works by enhancing and prolonging the actions of these nerves. An important part of this neural pathway is a group of nerve cells in the spinal cord that connects the central nervous system with peripheral nerves in the reproductive organs - these are called preganglionic neurons. Recently we discovered that a major pathway from the spinal cord to the pelvic blood vessels in females leaves the spinal cord at a different level (lumbar) from that thought previously (sacral level). Currently there is no information on how these lumbar preganglionic nerves in females are connected to other nerve pathways that are active during sexual activity, and how they integrate signals from both the internal organs and the brain. We will use an array of modern cellular techniques together with direct observation of dilation in isolated uterine arteries to discover how these nerve cells are wired up in circuits in the spinal cord. This information is vital for us to understand the factors producing increased blood flow in normal sexual activity, and how these might be altered in inflammation or in conditions where there could be selective damage to one nerve pathway and not the other, such as after pelvic surgery, spinal cord damage at different levels, or stimulation of the spinal cord for treatment of chronic pain. Our study also will help understand referred pain and sensations of discomfort in abdominal and pelvic organs.Read moreRead less