Regulation Of Cellular Responses To Neuropeptides.
Funder
National Health and Medical Research Council
Funding Amount
$83,510.00
Summary
Neuropeptides are chemicals released from nerves that are responsible for communication between the nerves, glands, muscles or other nerves. Neuropeptides exert their diverse biological effects by interacting with small structures on the cells they wish to communicate with. These structures bind the neuropeptide and are termed neuropeptide receptors. The responses of tissues to neuropeptides, for example, contraction of muscle, decrease with continued exposure to the neuropeptide. This reduction ....Neuropeptides are chemicals released from nerves that are responsible for communication between the nerves, glands, muscles or other nerves. Neuropeptides exert their diverse biological effects by interacting with small structures on the cells they wish to communicate with. These structures bind the neuropeptide and are termed neuropeptide receptors. The responses of tissues to neuropeptides, for example, contraction of muscle, decrease with continued exposure to the neuropeptide. This reduction in response is termed desensitization is thought to turn off the response to cells following stimulation by neuropeptides. In this study, I will investigate the mechanisms behind the desensitization of VPAC receptors which are a found throughout the body and have many important roles for example, gastrointestinal, pancreatic and reproductive function and control of muscle. VPAC receptors are also highly expressed in certain many cancers such as breast, prostate and colon carcinoma. The wide variety of functions that these receptors perform and the wide distribution in the body suggest that these are very important receptors. To date research into the responses and desensitisation of these receptors has been lacking, and the work that has been done has become confusing as more receptors and neuropeptides which bind them are discovered. The current project aims to carefully study these receptors and to determine their role in health and disease. The understanding the interaction of receptor and neuropeptide can perhaps lead to development of new therapeutic agents.Read moreRead less
Roles Of The Peptide Hormone, Ghrelin, In The Spinal Cord
Funder
National Health and Medical Research Council
Funding Amount
$414,326.00
Summary
This study investigates the control of internal organs of the body, the heart, blood vessels, intestine and bladder. We have made the new and surprising discovery that ghrelin, previously known to be a hormone, is probably also a neurotransmitter in the spinal cord. This raises the possibility that drugs that act on ghrelin receptors in the spinal cord could be used to treat high blood pressure or other problems of internal organs.
Mechanosensitive Afferent Nerves And Gastrointestinal Motility
Funder
National Health and Medical Research Council
Funding Amount
$384,693.00
Summary
This project aims to identify the different types of sensory nerves from the gut which cause sensations such as fullness, nausea or pain. These sensory nerves also activate important reflexes that coordinate different regions of the gut to ensure that food is properly digested and propelled. Many studies have examined these sensory nerves and how they can be activated by stretching the gut wall, but very basic questions remain to be answered. We do not know how many different types of sensory ne ....This project aims to identify the different types of sensory nerves from the gut which cause sensations such as fullness, nausea or pain. These sensory nerves also activate important reflexes that coordinate different regions of the gut to ensure that food is properly digested and propelled. Many studies have examined these sensory nerves and how they can be activated by stretching the gut wall, but very basic questions remain to be answered. We do not know how many different types of sensory nerves there are and whether they all respond to stretch in the same way. We cannot identify their specialised endings in the wall of the gut. While these sensory nerves definitely respond to stretch, they are also known to respond to contractions of the gut wall. Despite this, we do not understand how the normal movements of the gut wall activate them, nor why some movements can lead to pain. Most of the experiments will be carried out on small pieces of tissue taken from humanely killed guinea pigs and studied, under highly controlled conditions, in organ baths. The remainder of the study will be on specimens of human gut tissue obtained at surgery. This project will use new techniques to record sensory nerves during both stretch and contraction of the gut wall to understand what activates them. In addition, their endings will be labelled with dye to reveal their different shapes. Using computerised imaging techniques we will identify whether they respond to particular patterns of movement in the gut wall. Lastly we will record from these sensory neurones in live specimens of human colon to see whether the same types of sensory nerves are present in humans as in the small animals. This study will provide the first comprehensive account of sensory nerves to the gut wall that respond to distension, including those that activate pain pathways. This is a pre-requisite for designing new drugs that will target these nerve cells with minimal side effects.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.
Integrative Properites Of Intrinsic Sensory Neurons Of The Intestine
Funder
National Health and Medical Research Council
Funding Amount
$211,681.00
Summary
For the neuronal control of the intestine to be appropriate to the constantly changing state of the organ, it is essential that there is feedback concerning, amongst other things, distension by its contents and its contractile state. These properties of the intestine are monitored by intrinsic sensory neurons, which are very special sensory cells, because they are embedded in the wall of the organ that they control. They have only very recently been identified, and thus surprisingly little is kn ....For the neuronal control of the intestine to be appropriate to the constantly changing state of the organ, it is essential that there is feedback concerning, amongst other things, distension by its contents and its contractile state. These properties of the intestine are monitored by intrinsic sensory neurons, which are very special sensory cells, because they are embedded in the wall of the organ that they control. They have only very recently been identified, and thus surprisingly little is known about how they perform their functions. It is clear, however, that they have special ways of integrating information about their environment, and the activities of other neurons, that are not shared by any other sensory neurons identified to the present time. Thus investigation of these neurons will provide information that is almost completely lacking about how the intestine performs its tasks. This information will be valuable in defining targets for development of therapeutic compounds and in analysing disorders of intestinal motility.Read moreRead less
Participation Of Intrinsic Sensory Neurons In The Initiation Of Colonic And Gastric Reflexes
Funder
National Health and Medical Research Council
Funding Amount
$109,448.00
Summary
The gastrointestinal tract adjusts its digestive activity in response to the food that we eat. To do this, the bulk and chemical composition of the food and products of digestion must be sensed. In the small intestine, this sensing is by neurons in the wall on the intestine (intrinsic neurons) and by neurons with cells outside the intestine and endings in its wall (extrinsic neurons). There is evidence for there being intrinsic sensory neurons in the colon, subserving fewer functions than in the ....The gastrointestinal tract adjusts its digestive activity in response to the food that we eat. To do this, the bulk and chemical composition of the food and products of digestion must be sensed. In the small intestine, this sensing is by neurons in the wall on the intestine (intrinsic neurons) and by neurons with cells outside the intestine and endings in its wall (extrinsic neurons). There is evidence for there being intrinsic sensory neurons in the colon, subserving fewer functions than in the small intestine, but direct recordings from putative colonic intrinsic sensory neurons during sensory stimuli have not been made. The literature does not indicate whether there are intrinsic sensory neurons in the stomach. Some data suggests they may be present only in the antrum. It is important to determine whether there are intrinsic sensory neurons in the colon and stomach, which seems likely, to identify them morphologically and physiologically, and to investigate their responsiveness to physiological sensory stimuli. These data may be useful to understand the pathogenesis of functional bowel disorders, including delayed emptying in the stomach (which occurs in diabetes, for example) and slow transit constipation. Proper identification and characterisation of intrinsic sensory neurons might guide the development of therapies for disorders of colonic and gastric motility.Read moreRead less
Migration And Differentiation Of Enteric Neuron Precursors
Funder
National Health and Medical Research Council
Funding Amount
$385,116.00
Summary
There are many millions of nerve cells within the wall of the intestine, and they control many intestinal functions, including motility. During development, these nerve cells arise from cells which migrate away from the developing brain and first enter the stomach. The migratory cells are called neural crest cells. After entering the stomach, neural crest cells migrate within the wall of the gastrointestinal tract, until they reach the far (anal) end. In embryonic mice, this colonisation of the ....There are many millions of nerve cells within the wall of the intestine, and they control many intestinal functions, including motility. During development, these nerve cells arise from cells which migrate away from the developing brain and first enter the stomach. The migratory cells are called neural crest cells. After entering the stomach, neural crest cells migrate within the wall of the gastrointestinal tract, until they reach the far (anal) end. In embryonic mice, this colonisation of the entire small and large intestines by neural crest cells takes over 4 days, and in humans the process probably takes at least one week. It is essential that the neural crest cells colonise the entire gastrointestinal tract, since regions of intestine lacking neural crest cells (and hence nerve cells) cannot function and intestinal contents build up in front of the region lacking nerve cells. This condition is found in some babies (Hirschsprung's disease), and it can only be treated by surgically removing the region lacking nerve cells. It is therefore essential that migratory neural crest cells colonise the entire gastrointestinal tract. Currently, little is known about the mechanisms controlling the migration of neural crest cells, and whether a) particular molecules within the gut wall are important for migration, and-or b) the migratory behaviour of the neural crest cells is regulated mostly by the neural crest cells themselves. In this study we will take time-lapse images of neural crest cells migrating through the gut of embryonic mice to identify the factors that are important for the migration. After the neural crest cells have colonised the entire intestine, they develop into different types of nerve cells. We will also examine some of the factors affecting the development of different types of nerve cells.Read moreRead less
Mechanisms Of Long Term Excitability Changes In Enteric Neurons
Funder
National Health and Medical Research Council
Funding Amount
$308,250.00
Summary
The intestine contains within its walls a nerve circuitry, the enteric nervous system, that controls many of its activities. The intestine itself adapts to circumstances, such as diet, and to pathological changes, such as infection or inflammation. In fact, changes in the intestine can outlast the events that cause them. This implies that there are prolonged changes in properties of control systems in the intestine. We have discovered that the intrinsic sensory neurons of the intestine exhibit l ....The intestine contains within its walls a nerve circuitry, the enteric nervous system, that controls many of its activities. The intestine itself adapts to circumstances, such as diet, and to pathological changes, such as infection or inflammation. In fact, changes in the intestine can outlast the events that cause them. This implies that there are prolonged changes in properties of control systems in the intestine. We have discovered that the intrinsic sensory neurons of the intestine exhibit long-term excitability increases following prolonged, low frequency, stimulation of their inputs from other neurons. This phenomenon has been called sustained slow postsynaptic excitation (SSPE). We have begun to examine the mechanisms behind the SSPE, and have discovered that it involves the enzymatic modification of molecules in the intrinsic sensory neurons. In this work, we will identify the enzymes and their molecular targets. This will add to basic knowledge of how the digestive system performs its task and adapts over time. It will provide data that can be used to predict molecules that might be of therapeutic value in dealing with chronic disorders in the intestine, such as irritable bowel syndrome.Read moreRead less
Neural Mechanisms Mediating Hypersecretion And Motility Patterns Induced By Enterotoxins
Funder
National Health and Medical Research Council
Funding Amount
$415,250.00
Summary
This project aims to identify the nerve cells that are responsible for the massive oversecretion of water and salt seen with cholera and other diseases producing diarrhoea. Many of these disease act through specific toxins and, although the biochemical targets of these toxins are reasonably well understood, the nerve cells on which they act have never been identified. Furthermore, the mechanisms that couple the oversecretion with a massive increase in the propulsive activity of the intestine are ....This project aims to identify the nerve cells that are responsible for the massive oversecretion of water and salt seen with cholera and other diseases producing diarrhoea. Many of these disease act through specific toxins and, although the biochemical targets of these toxins are reasonably well understood, the nerve cells on which they act have never been identified. Furthermore, the mechanisms that couple the oversecretion with a massive increase in the propulsive activity of the intestine are also unknown. We will investigate each of these questions using the small intestine of the guinea-pig, because the nerve circuit in this preparation is better understood than that of any other. Nerve cells that respond to three specific toxins, each known to activate the nervous system via different mechanisms, will be determined using intracellular recording methods, injection of marker dyes and methods that allow the identification of their neurochemistry. This will allow the functions of responsive nerve cells to be identified and their places in the circuits that control secretion and propulsion to be determined. This information will be correlated with studies in whole animals being undertaken in Sweden so that potential sites for intervention can be identified.Read moreRead less
Characterisation Of Ion Channels That Are Potential Therapeutic Targets In Enteric Neurons
Funder
National Health and Medical Research Council
Funding Amount
$535,141.00
Summary
Disorders of intestinal movement (motility) are common and cause considerable suffering, absenteeism and social disruption. Disorders include motility disturbances that occur in irritable bowel syndrome (IBS); constipation, which is a considerable problem in the aged; slow transit disorders; and diarrhoea. The movements of the intestine are controlled by the enteric nervous system. This project aims to find targets for therapy of motility disorders within the enteric nervous system