Heartbeats are considered to arise through specialised pacemaker cells establishing rhythmically generated (i.e. pacemaker) action potentials, which then trigger propagating action potentials in heart muscle causing contraction and pumping of blood. This research proposal aims to challenge the physical model that is used to describe this pacemaker process and resultant heart conduction. Our reasons for doing this derive from our discovery of an alternative pacemaker-conduction mechanism, which w ....Heartbeats are considered to arise through specialised pacemaker cells establishing rhythmically generated (i.e. pacemaker) action potentials, which then trigger propagating action potentials in heart muscle causing contraction and pumping of blood. This research proposal aims to challenge the physical model that is used to describe this pacemaker process and resultant heart conduction. Our reasons for doing this derive from our discovery of an alternative pacemaker-conduction mechanism, which we have shown to operate in various smooth muscles. This mechanism, termed store-based pacemaking, is entirely different to the currently held cardiac model but could readily achieve the same outcome. We will investigate the hypotheses that this pacemaker mechanism is also fundamental to mammalian heart pacemaking and conduction. Positive support for our hypotheses, as indicated by our findings on amphibian hearts and from pilot findings, may severely challenge the present model for cardiac pacemaking. Such an outcome will have major ramifications on present interpretation of cardiac function in health and disease and will be particularly important to interpretation of disorders associated with cardiac arrhythmias and heart conduction.Read moreRead less
Intramuscular Interstitial Cells Of Cajal; Ion Channels And Their Modulation By Calcium Ions And Neurotransmitters.
Funder
National Health and Medical Research Council
Funding Amount
$523,261.00
Summary
Disorders of gut motility manifest themselves in several ways, as either patterns of hyperactivity or patterns of reduced activity. Under normal conditions gut motility reflects a balance between myogenic, neuronal and hormonal factors but as yet how this balance is normally achieved is not understood. This project will examine the properties of a class of cells, whose importance in both myogenic and neural control mechanisms has only been recognized over the last 10 years. The muscular wall of ....Disorders of gut motility manifest themselves in several ways, as either patterns of hyperactivity or patterns of reduced activity. Under normal conditions gut motility reflects a balance between myogenic, neuronal and hormonal factors but as yet how this balance is normally achieved is not understood. This project will examine the properties of a class of cells, whose importance in both myogenic and neural control mechanisms has only been recognized over the last 10 years. The muscular wall of the gut is made up of two distinct types of cells. One group, smooth muscle cells, contains contractile elements and the coordinated behavior of these cells leads to the contractions of the gut wall, so ensuring the controlled passage of gut contents along the gastrointestinal tract. The other group of cells, Interstitial cells of Cajal, lack contractile elements. One set of these cells have recently been found to be the pacemaker cells of the gut responsible for the initiation of myogenic activity. They generate pacemaker waves which ensure that the gut contracts rhythmically. Another set of these cells are densely innervated, they receive messages from the nervous system and translate these messages into signals which alter the activity of the gut. Thus these cells play a key role in the neural control of the gut. In many disease states, the numbers of interstitial cells of Cajal have been found to be reduced. However as yet we know very little about these cells. This project will, for the first time, examine the properties of the interstitial cells involved in neural control and will determine how they carry out these essential functions.Read moreRead less
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
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
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
Gastrointestinal Signals And Cardiovascular Regulation- Implications For Obesity-related Hypertension.
Funder
National Health and Medical Research Council
Funding Amount
$486,886.00
Summary
Obesity is reaching epidemic proportions, and obesity-related hypertension is the leading cause of serious cardiovascular complications. Hormones released from the gut have been implicated in obesity, but their contribution to hypertension has not been studied. Preliminary studies in our laboratory have shown that these hormones participate in signals related to cardiovascular control by acting locally to relay signals to the brain, and may be more important in obesity than previously thought.
In this grant we will take advantage of procedures uniquely available to the applicant to identify the cell type from which the most prevalent extra cranial solid tumour in children, neuroblastoma (NB), arises during embryonic development. Further studies on this specific cell type will identify the factors controlling their correct embryonic development. Assessment of these molecules as therapeutic targets will then identify novel treatments to inhibit disease progression.
Control Of Sympathetic Nerves That Talk To The Immune System
Funder
National Health and Medical Research Council
Funding Amount
$385,958.00
Summary
The two complex systems of the body, the immune system and the nervous system, communicate with each other. This proposal studies one of the major pathways from brain to immune system - sympathetic immuno-efferent nerves. In stroke, these pathways cause profound immunosuppression, causing susceptibility to infection. Their poorly understood central and peripheral pathways will be defined and mapped by this study.
Regeneration Of Pelvic Autonomic Axons After Injury
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
This project is focused on the problem of erectile dysfunction, especially the common situation where this is caused by injury to the penile nerves. These nerves are part of the parasympathetic nervous system . Nerve injury-induced erectile dysfunction is a common problem for prostatectomy patients, with recovery of normal erections occurring slowly, partially or not at all. There is currently no therapy to improve regeneration of these nerves, and this is partly because very little is known abo ....This project is focused on the problem of erectile dysfunction, especially the common situation where this is caused by injury to the penile nerves. These nerves are part of the parasympathetic nervous system . Nerve injury-induced erectile dysfunction is a common problem for prostatectomy patients, with recovery of normal erections occurring slowly, partially or not at all. There is currently no therapy to improve regeneration of these nerves, and this is partly because very little is known about effects of injury on any parasympathetic neurons, and especially for those that are essential for erection. The first aim of this study is to define the key structural and functional changes occurring in penile parasympathetic neurons during regeneration after injury. This fundamental neurobiological knowledge is essential to develop and optimise an future growth treatments. The second aim of the study is to define the effects of a protein, neurturin, on axonal regeneration of penile pro-erectile neurons. Our evidence so far strongly suggests that it is necessary for the early stages of injury responses. Our studies will be performed in mice, where we also have colonies of knockout animals to study the effect of removing neurturin from the regeneration process. Our experiments will include neuroanatomical studies of injured and growing nerves, pharmacology studies on penile smooth muscle (corpus cavernosum) innervation and responsiveness, and tissue culture studies. We will investigate not only the changes that occur following injury to penile nerves, but also the way in which undamaged nerves may assist in returning erectile function.Read moreRead less
This project aims to discover the nervous pathways and mechanisms in the brain that control body temperature. We hope to identify the nerve cells in the brain that detect increases in the core temperature of the body and determine the nervous pathways that project from them to increase blood flow to the skin when we become hot. This research may lead to a better understanding of heat exhaustion which is especially dangerous to the elderly.