Altered HCN Channel Expression And Function In Acquired Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$279,912.00
Summary
About 100 000 people currently suffer from epilepsy in Australia and of these about one third are poorly controlled with current anti-epileptic drugs. It is therefore important to continue to develop novel modes of treatment for this debilitating disease. This projects investigates an ion channel, known as the HCN channel, that is thought to be involved in making a brain epileptic. We explore how changes in this channel can make a brain more excitable. Also, our group is the first in the world t ....About 100 000 people currently suffer from epilepsy in Australia and of these about one third are poorly controlled with current anti-epileptic drugs. It is therefore important to continue to develop novel modes of treatment for this debilitating disease. This projects investigates an ion channel, known as the HCN channel, that is thought to be involved in making a brain epileptic. We explore how changes in this channel can make a brain more excitable. Also, our group is the first in the world to discover a mutation in this channel that is linked to epilepsy. We will also investigate how this mutation changes the channel properties to make a brain more likely to be epileptic. The HCN channel is an important target for developing anti-epileptic drugs. Understanding how changes in HCN channels make nerve cells and therefore nerve cell networks more excitable will help us develop better strategies for designing anti-epileptic drugs.Read moreRead less
Noradrenaline Transporter Dysfunction In Neural Circulatory Disorders: Clinical, Molecular And Therapeutic Implications
Funder
National Health and Medical Research Council
Funding Amount
$510,870.00
Summary
We will investigate the clinical relevance of noradrenaline transporter (NET) dysfunction and its molecular and genetic regulation in (1) essential hypertension, (2) postural tachycardia syndrome where the heart rate increases abnormally when the patient assumes an upright position and (3) syncope where subjects experience recurrent blackouts. In a therapeutic approach, we will explore whether NET inhibition can reduce the number of episodes and alleviate the symptoms associated with syncope.
Panic Disorder: Neurobiology And Mechanisms Of Cardiac Risk
Funder
National Health and Medical Research Council
Funding Amount
$456,657.00
Summary
Some people are subject to episodes of recurring, often inexplicable anxiety which are very unpleasant and accompanied by physical symptoms such as sweating, palpitations, tremor and a sensation of suffocation. Recurring attacks over a period of months, or years, forms the basis for the diagnostic of panic disorder. It has until recently been felt that although panic disorder was distressing and disabling, it did not constitute a risk of life. Sufferers often fear that they have heart disease, b ....Some people are subject to episodes of recurring, often inexplicable anxiety which are very unpleasant and accompanied by physical symptoms such as sweating, palpitations, tremor and a sensation of suffocation. Recurring attacks over a period of months, or years, forms the basis for the diagnostic of panic disorder. It has until recently been felt that although panic disorder was distressing and disabling, it did not constitute a risk of life. Sufferers often fear that they have heart disease, because of the nature of their symptoms, but have been reassured that this is not the case. Recent epidemiological studies, however, indicate that there is an increased risk in patients with panic disorder. Our hypotheses in this research project are as follow: That some specific genes predispose to the development of panic disorder - through actions on the nervous system and blood vessels That drug treatment (selective serotonin uptake blockers) and psychological treatment (cognitive behaviour therapy, CBT) reduce cardiac risk in panic disorder We will test these hypothesis using state of the art clinical scientific methods. Panic disorder has an important cardiological dimension which needs to be better understood for cardiac protection to be achieved in panic disorder patients.Read moreRead less
Panic Disorder: Neurobiology And Mechanisms Of Cardiac Risks
Funder
National Health and Medical Research Council
Funding Amount
$414,375.00
Summary
Some people are subject to episodes of recurring, often inexplicable anxiety which are very unpleasant and accompanied by physical symptoms such as sweating, palpitations, tremor and a sensation of suffocation. Recurring attacks over a period of months, or years, forms the basis for the diagnosis of panic disorder. It has until recently been felt that although panic disorder was distressing and disabling, it did not constitute a risk to life. Sufferers often fear that they have heart disease, be ....Some people are subject to episodes of recurring, often inexplicable anxiety which are very unpleasant and accompanied by physical symptoms such as sweating, palpitations, tremor and a sensation of suffocation. Recurring attacks over a period of months, or years, forms the basis for the diagnosis of panic disorder. It has until recently been felt that although panic disorder was distressing and disabling, it did not constitute a risk to life. Sufferers often fear that they have heart disease, because of the nature of their symptoms, but have been reassured that this is not the case. Recent epidemiological studies, however, indicate that there is an increased risk of heart risk in patients with panic disorder. Our hypotheses in this research are as follows: That panic disorder is characterised by increased release of the brain chemical messenger, serotonin, which is reversed by drug treatment with the most widely used class of drugs for this disorder, selective serotonin reuptake blockers That changes in an automatic stimulatory part of the nervous system, has primary importance in the disorder, in both genetically predisposing to panic disorder, and in mediating heart risk. That weight gain during therapy, a very common problem, is due to inhibition of brain serotonin release. We will test all these propositions using state of the art clinical scientific methods. Panic disorder has an important cardiological dimension which needs to be better understood for cardiac protection to be achieved in panic disorder patients. Our study of the mechanisms of cardiac risk should provide this. We will also provide very direct, valid measurements of chemical messenger release in the brain of panic disorder sufferers, using our unique methods. These should give a new understanding of the brain chemistry abnormalities of panic disorder, and the mechanism of action of the selective serotonin reuptake inhibitors.Read moreRead less
Cellular Mechanisms Controlling Neural Crest Cell Migration Along The Developing Gut
Funder
National Health and Medical Research Council
Funding Amount
$368,895.00
Summary
Within the wall of the gut, there are a large number of neurons, probably more than are in the spinal cord. These enteric neurons play an essential role in controlling a number of gut functions including peristalsis (the propulsion of contents along the gut). Most of the neurons in the gut, including those in the large intestine, arise from precursors that emigrate from the hindbrain, and then migrate into and along the gastrointestinal tract during development. The colonization of the gut by ne ....Within the wall of the gut, there are a large number of neurons, probably more than are in the spinal cord. These enteric neurons play an essential role in controlling a number of gut functions including peristalsis (the propulsion of contents along the gut). Most of the neurons in the gut, including those in the large intestine, arise from precursors that emigrate from the hindbrain, and then migrate into and along the gastrointestinal tract during development. The colonization of the gut by neuron precursors takes 5 days in mice and 6 weeks in humans. Studies of the mechanisms controlling the migration of neuron precursors along the gut have provided fundamental information about cell migration in general. Genetic studies in humans and mice have identified some of the genes that are necessary for the migration of neuron precursors along the gastrointestinal tract, but for some of the key genes, their precise role is unknown. We have recently developed a method for imaging living neuron precursors migrating through explants of embryonic mouse gut. In the current proposal we will meld imaging and genetic studies to understand how mutations in particular genes lead to migration defects. In particular, how do particular mutations affect the migratory behaviour of enteric neural precursors? We have also previously shown that neuron precursors migrate along the gut in close association with axons. We will examine the nature of these interactions - in particular, who is following whom, and what happens when cell migration and axon growth are uncoupled? These studies, which will investigate a number of critical aspects of the migration of neural precursors into and along the developing gut, are central to understanding how the enteric nervous system is established along the gastrointestinal tract.Read moreRead less
Cardiovascular Responses To Stress And Arousal: Hypothalamic And Brainstem Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$566,468.00
Summary
Stressful episodes in everyday life cause increases in blood pressure, mainly via activation of nerves that constrict blood vessels and increase heart rate. This in turn increases the risk of heart attacks, strokes, or other cardiovascular diseases. This project aims to identify the brain mechanisms that cause these stress-evoked effects. This knowledge may lead to much more effective ways of minimising stress-evoked responses, and thus reduce the risk of cardiovascular disorders.
Importance Of The Brain Renin-Angiotensin System For Regulating Blood Pressure And Cardiovascular Autonomic Function.
Funder
National Health and Medical Research Council
Funding Amount
$609,424.00
Summary
The peptide angiotensin a major regulator of many brain areas controlling blood volume and blood pressure. Brain angiotensin may well contribute to high blood pressure but how it acts in each of the different brain areas is unknown. New gene transfer technology using viruses combined with genetically modified mice will enable this project to inactivate or activate angiotensin in each brain nucleus and determine the role of individual areas to setting of blood pressure leading to hypertension.
Migratory Cells To Ganglionated Network: Self-organization Of The Enteric Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$328,294.00
Summary
The intestine has its own nervous system. This develops from cells that wander into the intestine during early development and self-organize to form the functional nervous system . The correct organization of the cells of this nervous system is required for correct intestine function. How they self-organize is not known, and there are diseases in which the process is disturbed. Molecular and cell biology and mathematical modelling will be used to understand how this occurs.
Nerve cells have unique properties like their ability to put out axons that reach long distances from the cell body (differentiation), their ability to make contacts with other cells and initiate communication by the release of neurotransmitters from synaptic vesicles inside nerve endings (exocytosis) and the recycling of those synaptic vesicles (endocytosis). These events are mainly controlled by a large number of synapse-specific proteins, and partly regulated by a signalling molecule, cGMP, w ....Nerve cells have unique properties like their ability to put out axons that reach long distances from the cell body (differentiation), their ability to make contacts with other cells and initiate communication by the release of neurotransmitters from synaptic vesicles inside nerve endings (exocytosis) and the recycling of those synaptic vesicles (endocytosis). These events are mainly controlled by a large number of synapse-specific proteins, and partly regulated by a signalling molecule, cGMP, which mainly stimulates the enzyme PKG. In previous studies supported by the NHMRC we identified many proteins that are phosphorylated and activated by PKG. One of them, septin 3, is the focus of this proposal. We initially cloned septin 3 as a new member of a family of 10 genes that are essential for cell division. Some septins assemble as filaments that allow the two new daughter cells to finally separate. When the filament formation is perturbed certain septins end up in microscopic clumps that are found in the post-mortem brains of people affected by Alzheimer's disease, suggesting they might contribute to the disease. However, septin 3 is unlike most septins because it is a brain-specific septin, which we found in neurons and found to be highly concentrated in nerve terminals, locations not normally associated with cell division. The only other known brain-specific septin, CDCrel-1, regulates the protein machinery of exocytosis. We will examine the hypothesis that G-septin is also a regulator of synaptic vesicle endocytosis. We will determine whether septin represents a convergence point for cGMP signalling to control endocytosis. A better understanding of septin 3 and endocytosis is crucial to understanding brain disorders and ultimately developing better therapies.Read moreRead less
The Function Of Dynamin Phosphorylation Sites In Synaptic Vesicle Endocytosis
Funder
National Health and Medical Research Council
Funding Amount
$794,565.00
Summary
Neurons communicate with each other via the release of neurotransmitters which are packaged in synaptic vesicles inside nerve endings. There are a finite number of vesicles, so they are recycled (endocytosis) for reuse. Synaptic vesicle exocytosis is very fast and normally endocytosis is a little slower, mopping up the used vesicles. Recently we showed that endocytosis can control synaptic transmission, hence it's an integral part of an overall cycle of synaptic transmission. We found that when ....Neurons communicate with each other via the release of neurotransmitters which are packaged in synaptic vesicles inside nerve endings. There are a finite number of vesicles, so they are recycled (endocytosis) for reuse. Synaptic vesicle exocytosis is very fast and normally endocytosis is a little slower, mopping up the used vesicles. Recently we showed that endocytosis can control synaptic transmission, hence it's an integral part of an overall cycle of synaptic transmission. We found that when endocytosis cannot keep up then exocytosis slows, greatly reducing the function of neurons. A complete block would result in paralysis of brain and muscles. Our team has been revealing the underlying molecular mechanisms of endocytosis in order to better understand diseases of the synapse like schizophrenia, epilepsy and Alzheimer's disease. We discovered that endocytosis is a regulated process at the heart of which is a pair of phosphorylation sites (points of phosphate attachment) in the key protein dynamin I. Our hypothesis is that endocytosis occurs in two forms, fast and slow. We propose to test the idea that proteins that associate with dynamin via the phosphorylation sites determine whether the fast or slow mode is used. Additionally, we propose that the first phosphorylation site is the trigger for endocytosis, while the second serves to recruit reserve supplies of dynamin to support the slow mode when it's required. A better understanding of Dyn and endocytosis is crucial to understanding brain disorders of synaptic transmission and ultimately for developing therapies. For example, a seizure is the uncontrolled firing of neurons. Our overall aim is to understand the control mechanisms of nerve communication to ultimately allow us to treat disorders of nerve communication like epilepsy.Read moreRead less