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
Do Postjunctional Alterations Explain The Effects Of Diabetes On Neurovascular Transmission?
Funder
National Health and Medical Research Council
Funding Amount
$390,886.00
Summary
Diabetes produces disordered skin blood flow that increases risk of skin ulcers and gangrene. The project investigates nervous control of skin blood vessels in diabetes. It is assumed that all affects of diabetes on nerve function are explained by loss of nerves. We hypothesize that some affects of diabetes are due to dysfunction of blood vessels and not to nerve loss. The objective is to identify drug targets to improve blood flow in skin and thereby reduce the risk of skin ulcers and gangrene.
Very little is known about mechanisms whereby depression harms the heart. This is especially disturbing as recent evidence indicates that while antidepressants alleviate a depressed persons negative mood, they do not eliminate danger to the heart. We will use an animal model to determine: How depression affects the electrical stability of the heart; The identity of the brain mechanisms that are involved; and which drugs can be used to protect the heart fro the harmful effects of depression.
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.
Changes In Pelvic Autonomic Neurons After Spinal Nerve Injury
Funder
National Health and Medical Research Council
Funding Amount
$176,734.00
Summary
This project is about the effects of spinal injury on autonomic neurons that control the bladder, lower bowel and reproductive organs. One of the consequences of some types of spinal injury is that there are no signals being sent from the spinal cord to the nerve cells outside the cord, and this leads to poor bladder control, impotence, etc. We are mimicking this problem experimentally by damaging the spinal nerves that carry these signals. We have found that after this type of damage the pelvic ....This project is about the effects of spinal injury on autonomic neurons that control the bladder, lower bowel and reproductive organs. One of the consequences of some types of spinal injury is that there are no signals being sent from the spinal cord to the nerve cells outside the cord, and this leads to poor bladder control, impotence, etc. We are mimicking this problem experimentally by damaging the spinal nerves that carry these signals. We have found that after this type of damage the pelvic autonomic neurons make many new connections between each other, and the types of new connections depend on which spinal nerves have been injured. This leads to the question: are these new connections good or bad? ie are they helpful in trying to get organ control back to normal or will they stop the correct connections from the spinal cord from being made in the future? This project addresses these questions by using sophisticated techniques for staining and visualising individual nerve fibres growing out from the spinal cord. We will track how well these fibres grow back and connect with the pelvic autonomic neurons. In particular, we will see whether they make correct connections, and if these connections are influenced by the new fibres that have grown between the autonomic neurons in the interim period. We will also do physiological tests to see if the new connections have the correct function. The ultimate aim of these studies is not only to understand more about regeneration, but to see what determines whether the correct connections have been made - and ideally, to give us insight into how we can make regeneration work more quickly and accurately. We believe that this work is an important adjunct to other studies on spinal injury, which mostly focuses on regaining voluntary motor control (e.g. walking); however loss of bladder, bowel and reproductive function is another important quality of life issue for spinal injury patients.Read moreRead less
The sphincter of Oddi is a valve-like structure, which regulates the flow of bile and pancreatic juice into the gut. The sphincter of Oddi is under complex control involving nerves and hormones. We know that abnormal sphincter of Oddi function (sphincter of Oddi dysfunction) is associated with a number of human diseases including acute pancreatitis. We are able to recognise abnormal sphincter activity, but we do not know what causes it. One possible reason may be that the nerves going to the sph ....The sphincter of Oddi is a valve-like structure, which regulates the flow of bile and pancreatic juice into the gut. The sphincter of Oddi is under complex control involving nerves and hormones. We know that abnormal sphincter of Oddi function (sphincter of Oddi dysfunction) is associated with a number of human diseases including acute pancreatitis. We are able to recognise abnormal sphincter activity, but we do not know what causes it. One possible reason may be that the nerves going to the sphincter along the bile duct (which carries bile from the liver and gallbladder) may be damaged due to the passage of gallstones or during surgery on the bile ducts or gallbladder. We know that the main bile duct is able to sense pressure changes within and communicate this information (via nerves) to the sphincter which inturn alters its activity to relieve the pressure. Where these nerves are located and the chemical messages they use, are unknown. The aim of this project is to gain some of this information. This knowledge may allow us to design different surgical procedures or develop drugs to prevent or manage the abnormal sphincter of Oddi.Read moreRead less
CENTRAL BLOCKADE OF SYMPATHETIC RESPONSES TO EMOTIONAL STRESSORS
Funder
National Health and Medical Research Council
Funding Amount
$313,933.00
Summary
Emotional stress triggers physiological reactions that affect our heart and blood pressure. For people with a weak or failing heart, this can lead to stroke and death. This project explores the effects and the sites of action in the brain of two different types drugs that could potentially reduce or prevent such accidents. Unlike the drugs that are currently in use, these two drugs act directly in the parts of the brain that control cardiovascular responses to emotional stress.
Convergent Regulation Of Sympathetic Neuronal Excitability By Peptide Hormones And Transmitters
Funder
National Health and Medical Research Council
Funding Amount
$498,465.00
Summary
This project will examine how hormones involved in regulating blood pressure interact with the nerves that control blood flow to the gut. We will combine electrical recordings of the activity of single nerve cells with an innovative new method of optically tracking the movements of single molecules, including hormons and neuronal messengers, that send signals to the nerve cells. Our results will reveal how blood pressure is normally maintained at healthy levels, even if we are ill.