Visceral Sensation In Complicated And Uncomplicated Upper Gastrointestinal Disease
Funder
National Health and Medical Research Council
Funding Amount
$66,929.00
Summary
50% of patients with complications of peptic ulcer (bleeding) and gastroesophageal reflux disease (Barrett's Oesophagus) have no symptoms of their diseases. In contrast, 50% of patients who seek treatment for gastrointestinal symptoms are found to have no cause after investigations. The aims of this study are to explore differences in sensation, muscular function and genetic factors between patients with functional gastrointestinal disorders and patients with complicated organic disorders.
We use a mouse model of inflammatory bowel disease (IBD) to determine how sensations from the inflamed gut are processed in the spinal cord. Over 60,000 Australians suffer from IBD and debilitating pain is a major symptom. Surprisingly, we know very little about how pain signals originating in the normal or the diseased gut are organised and processed in the central nervous system. Obtaining such information is a necessary first step before we can develop therapies to relieve gut pain.
How Does Inflammation Of The Gut Change Its Sensory Innervation?
Funder
National Health and Medical Research Council
Funding Amount
$613,767.00
Summary
A large number of patients that are referred to gastroenterologists for pain and discomfort from the bowel are offered no effective treatment. This has a large impact on quality of life and often involves invasive tests to rule out inflammatory or cancerous causes. These patients are classified as suffering from irritable bowel syndrome (IBS). Patients who have diagnosable inflammatory bowel disease (IBD) where colonoscopy is positive may suffer similar symptoms but also have no treatment for th ....A large number of patients that are referred to gastroenterologists for pain and discomfort from the bowel are offered no effective treatment. This has a large impact on quality of life and often involves invasive tests to rule out inflammatory or cancerous causes. These patients are classified as suffering from irritable bowel syndrome (IBS). Patients who have diagnosable inflammatory bowel disease (IBD) where colonoscopy is positive may suffer similar symptoms but also have no treatment for this type of symptom. It is becoming apparent that a large subgroup of IBS patients have undergone prior infection or inflammation, and that there are in fact changes in the types of cells in biopsies from their gut. Thus there are common features to IBS and inflammation. These may provide a means for us to find new treatments for IBS and IBD symptoms. Mice develop similar microscopic changes in the colon after experimental inflammation to those seen in humans, so we can discover more from this model. We have recently established that there are several types of sensory nerve fibres from the mouse colon and rectum that convey information about contractions, distension and chemical mediators released from tissue to the central nervous system. These are almost certainly responsible for generating symptoms in patients. We aim in this project to discover how these sensory nerves change in their responsiveness to mechanical and chemical stimuli in experimental inflammation. Importantly we shall investigate the mediators that are present in the tissue which may activate sensory nerves and-or the receptors on sensory nerves that may be increased. These experiments we hope will provide a target at which to aim novel drug treatments for symptoms of IBS and IBD.Read moreRead less
Mechanisms Of Mechanotransduction In Primary Visceral Afferents
Funder
National Health and Medical Research Council
Funding Amount
$253,500.00
Summary
Mechanotransduction is the process whereby mechanical stimuli are converted into signals in sensory nerves. This forms the basis of touch, hearing, position sense and many aspects of internal perception. It also constitutes a major component of pain. Our group aims to discover the molecular basis of mechanotransduction in mammals, and in particular how it relates to signaling of events in the digestive system. We and our collaborators have been among the first to explore this question, and have ....Mechanotransduction is the process whereby mechanical stimuli are converted into signals in sensory nerves. This forms the basis of touch, hearing, position sense and many aspects of internal perception. It also constitutes a major component of pain. Our group aims to discover the molecular basis of mechanotransduction in mammals, and in particular how it relates to signaling of events in the digestive system. We and our collaborators have been among the first to explore this question, and have found that three genes are responsible for many aspects of mechanotransduction. Each gene is transcribed to produce a channel or pore in the membrane of sensory nerve fibres which responds to mechanical forces by allowing ions to enter and induce electrical signals. Our early findings in mice with disruption of individual genes indicate that a complex positive and negative interaction of these channels must underlie normal mechanotransduction. However, these channels must represent only a part of the transduction mechanism, with extracellular and intracellular anchors inevitably playing a major role. The identity of such anchoring proteins in mammals is currently emerging, and we are fortunate to have access to mice deficient in specific genes that will provide information about candidates for this role. Through our studies on mechanotransduction in the digestive system in parallel with our collaborators' studies on mechanotransduction in skin we shall not only identify the fundamental mechanisms of mammalian mechanotransduction, but also reveal which components of mechanotransducers are peculiar to the gut. Such peculiarities provide molecular targets for therapy of diseases in which alteration of mechanosensory signaling is itself an aim.Read moreRead less
Strategies To Restore Bladder Control After Peripheral Nerve Injury
Funder
National Health and Medical Research Council
Funding Amount
$519,967.00
Summary
A major complication of pelvic surgery is loss of bladder control, mainly due to nerve injury at the time of removing cancerous tissue. This has a big effect on quality of life. Very little research has been conducted on injured bladder nerves. In this project we will investigate what happens to bladder nerves after injury and how we can make them regrow. We will also investigate if undamaged bladder nerves can be made to compensate for the lost function.
Neural Mechanisms In Tactile, Kinaesthetic And Pain Sensation
Funder
National Health and Medical Research Council
Funding Amount
$644,113.00
Summary
Our knowledge of the world around us depends upon our sensory systems which provide a series of windows on the world, enabling the mind and brain to sample information about selected events through the energy forms that impinge upon us. Much of this sensing process takes place through our special sense systems such as the eye, the ear, and the taste and olfactory systems. However, other crucial sensory systems are more generalized throughout the body and are referred to as the somatic sensory sy ....Our knowledge of the world around us depends upon our sensory systems which provide a series of windows on the world, enabling the mind and brain to sample information about selected events through the energy forms that impinge upon us. Much of this sensing process takes place through our special sense systems such as the eye, the ear, and the taste and olfactory systems. However, other crucial sensory systems are more generalized throughout the body and are referred to as the somatic sensory systems. These include our senses of touch, temperature, pain and body position, the last of which is known as our kinaesthetic sense. Our research into the neural mechanisms in sensation and perception is concerned with the tactile, kinaesthetic and pain senses. Although many thousands of nerve fibres travel in the nerves arising from particular regions of the skin or from individual muscles or joints, the sensory nerve fibres that serve these forms of sensation fall into fewer than ten broad classes, made up of five major tactile classes, two or three major kinaesthetic classes, and two broad groups of fibres that mediate pain sensation. However, there is quite striking evidence that when single fibres of these different classes are activated in conscious human subjects, there are marked differences among the fibre classes in their capacity to generate a perceptual response. Under the new NH and MRC grant we propose to examine the transmission and processing of input signals from these fibre classes at the highest levels of the brain, in particular, within the cerebral cortex, in order to reveal the neural mechanisms responsible for their differential perceptual contributions. The proposed analysis will provide fundamental insights into the neural basis for perceptual recognition and will provide information that may be important for our eventual understanding of the disorders of sensory perception that characterize psychiatric conditions such as schizophreniaRead moreRead less