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
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
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.
Distribution, Pharmacology, Molecular Identity And Roles Of Purine Receptors In Enteric Neurons
Funder
National Health and Medical Research Council
Funding Amount
$395,250.00
Summary
Digestive function needs to be adapted to the great variety of foods that we eat, and to our variable dietary habits. Adaptation is controlled through an extensive nervous system in the wall of the gastrointestinal tract, the enteric nervous system, and through digestive system hormones. The enteric nervous system detects the volume and key chemical components in the gastrointestinal lumen and, through an integrating nerve circuitry, causes changes in the patterns of movement, fluid secretion an ....Digestive function needs to be adapted to the great variety of foods that we eat, and to our variable dietary habits. Adaptation is controlled through an extensive nervous system in the wall of the gastrointestinal tract, the enteric nervous system, and through digestive system hormones. The enteric nervous system detects the volume and key chemical components in the gastrointestinal lumen and, through an integrating nerve circuitry, causes changes in the patterns of movement, fluid secretion and local blood flow. Digestive system diseases, for example irritable bowel syndrome, can involve disordered function of the enteric nervous system, and there is considerable research and development focus to identify drug targets in the enteric nervous system that can be used in therapy. Amongst potential targets are receptors for purines that are located on enteric neurons and are one of the important classes of receptor that is involved in communication between the neurons. These studies aim to identify the purine receptors, their roles in controlling digestive function and their potential as therapeutic targets in the treatment of digestive disease.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.
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 applicant aims to improve treatment of digestive disease by identifying and understanding the interactions between the nervous system and the gastrointestinal (GI) tract, with emphasis on sensory systems.
Gastrointestinal Sensory Function In Normal And Diseased States
Funder
National Health and Medical Research Council
Funding Amount
$691,026.00
Summary
Chronic pain and discomfort from the digestive system is a major health care issue world-wide. There is currently no effective treatment for these problems, which often have no apparent organic cause. Lack of treatment is due to a lack of understanding about how sensations are transmitted from the digestive system to the brain. Our research group has unique and powerful techniques that allow us to probe the basic mechanisms of sensory function, and make rapid progress towards finding drugs that ....Chronic pain and discomfort from the digestive system is a major health care issue world-wide. There is currently no effective treatment for these problems, which often have no apparent organic cause. Lack of treatment is due to a lack of understanding about how sensations are transmitted from the digestive system to the brain. Our research group has unique and powerful techniques that allow us to probe the basic mechanisms of sensory function, and make rapid progress towards finding drugs that reduce specific types of sensory signals from the gut. We shall investigate sensory mechanisms in the upper and lower regions of the gut, where symptoms are most prevalent in diseases such as non-cardiac chest pain, functional dyspepsia and irritable bowel syndrome. Six aspects of sensory nerve endings in the gut are to be investigated: 1. The grouping of endings into functional classes (similar to touch or pressure receptors in skin) 2. How endings respond to chemicals and hormones found in the gut 3. How currently available drugs may be useful in reducing sensitivity 4. The mechanisms by which inflammation affects sensitivity 5. How nerve growth factors may trigger changes in sensitivity 6. How pores or channels in nerve endings determine their functionRead moreRead less