Store-operated Calcium Channels And Liver Function
Funder
National Health and Medical Research Council
Funding Amount
$241,477.00
Summary
The liver is responsible for regulating the metabolism of carbohydrates and lipids , the synthesis of proteins responsible for the transport of lipids in the blood, the synthesis of bile required for fat digestion, and for the removal of toxic chemicals from the body. Many of these processes are regulated by the changes in the free calcium concentration in the cytoplasmic space of liver cells. In a number of diseases such as diabetes, fat malabsorption, and liver failure, the balance and regulat ....The liver is responsible for regulating the metabolism of carbohydrates and lipids , the synthesis of proteins responsible for the transport of lipids in the blood, the synthesis of bile required for fat digestion, and for the removal of toxic chemicals from the body. Many of these processes are regulated by the changes in the free calcium concentration in the cytoplasmic space of liver cells. In a number of diseases such as diabetes, fat malabsorption, and liver failure, the balance and regulation of calcium concentrations in liver cells is abnormal. The cytoplasmic calcium signal can come either from the extracellular space, through channels in plasma membrane, or from the intracellular calcium-storing organelles. The aims of the present proposal are to investigate the properties of the calcium channels in the liver cell plasma membrane, and the mechanisms by which they are regulated. The experiments will involve the direct estimation of calcium inflow into liver cells, measured as an electric current through the plasma membrane by patch-clamp technique. The results should show how calcium channels in liver cells work and provide knowledge that can be used for better treatment of diabetes, fat malabsorption and liver failure.Read moreRead less
Effects Of Mutations In The Conserved Cysteine Loop Of The GABA-A Receptor
Funder
National Health and Medical Research Council
Funding Amount
$417,750.00
Summary
Inhibiting excitatory signals in the brain is the function of large proteins called GABA-A receptors. Many general anaesthetics, tranquillisers and anti-epileptic drugs act by modulating GABA-A receptors. Modern surgery would not be possible without rendering patients unconscious with general anaesthetics. However, these valuable drugs can still have unwanted side effects: for example, some of them can affect cardiac and respiratory function. There is still a need for new, more effective general ....Inhibiting excitatory signals in the brain is the function of large proteins called GABA-A receptors. Many general anaesthetics, tranquillisers and anti-epileptic drugs act by modulating GABA-A receptors. Modern surgery would not be possible without rendering patients unconscious with general anaesthetics. However, these valuable drugs can still have unwanted side effects: for example, some of them can affect cardiac and respiratory function. There is still a need for new, more effective general anaesthetics. One in every 200 people in Europe and North America suffers from epilepsy and 3% of the population suffers from anxiety. Leading, currently used general anaesthetics, anxiolytic and anti-epileptic drugs act on GABA-A receptors in the brain. The potential annual market for these drugs has been estimated to be US $2.7 billion. The world market for anaesthetics in 1999 was US $1.6 billion. All were discovered serendipitously. If the molecular site and mode of action of these drugs were understood, it is possible that new, more selective drugs could be discovered. The information gained in this project about GABA-A receptors is expected to be useful in understanding how these receptors work and in developing a new generation of drugs acting on GABA-A receptors. Specific mutations in GABA-A receptors can have a profound influence on their function. Studying the effects of mutations is slowly giving us more information about the ion channel region and drug binding sites. Recently, mutations in GABA-A receptors have been found to be associated with some forms of epilepsy. In this project, we plan to examine the effects of mutations in highly conserved residues of a small region of subunits of the GABAA receptor because: (1) we (and others) have preliminary evidence that this loop forms a connection between the GABA binding site and the ion channel and (2) we think that this part of the receptor is vital for the effects of some drugs.Read moreRead less
The Functional Basis Of Direction Selectivity In The Retina
Funder
National Health and Medical Research Council
Funding Amount
$376,320.00
Summary
Motion is an everday visual experience, and in this project we are attempting to explain how our brains are able to detect the direction in which an object is moving. Surprisingly this is first accomplished within the retina, the light-sensitive system of neurons at the back of the eye. Thus the eyes are able to tell the brain in which direction an object is moving. So the question becomes, how do the eyes do it? We know that there is a special class of neurons, the direction-selective ganglion ....Motion is an everday visual experience, and in this project we are attempting to explain how our brains are able to detect the direction in which an object is moving. Surprisingly this is first accomplished within the retina, the light-sensitive system of neurons at the back of the eye. Thus the eyes are able to tell the brain in which direction an object is moving. So the question becomes, how do the eyes do it? We know that there is a special class of neurons, the direction-selective ganglion cells, which are able to detect the direction of image motion. The activity of these cells is increased by excitatory connections and reduced by so-called inhibitory connections. This project aims to identify the neural origin of the inhibitory connections, and discover how the excitation and inhibition work together to compute the direction of motion.Read moreRead less
Development Of Bacterial Mechanosensitive Channels As Nanodevices In Liposome Systems For Targeted Drug Delivery
Funder
National Health and Medical Research Council
Funding Amount
$502,341.00
Summary
Liposomes are among the most advanced mainstream particulate drug carriers in modern medicine. They vary in complexity, but in their most basic form consist of naturally occurring phospholipid vesicles, capable of encapsulating a wide range of drugs. Such liposomes provide a high degree of biocompatibility and a physical barrier that protects the drug cargo from degradative enzymes in the patient. Furthermore, liposomes provide an effective, non-toxic method to solubilise hydrophobic drugs and a ....Liposomes are among the most advanced mainstream particulate drug carriers in modern medicine. They vary in complexity, but in their most basic form consist of naturally occurring phospholipid vesicles, capable of encapsulating a wide range of drugs. Such liposomes provide a high degree of biocompatibility and a physical barrier that protects the drug cargo from degradative enzymes in the patient. Furthermore, liposomes provide an effective, non-toxic method to solubilise hydrophobic drugs and administer potent and even highly toxic drugs such as the anthracyclines, Doxorubicin and Daunorubicin (clinically approved anti-cancer treatments), Amphotericin B (fungal disease therapy) and Taxol (cancer therapy).The focus of this project is to incorporate nanovalves into these drug delivery systems, in the form of bacterial mechanosensitive (MS) channels, to facilitate the controlled and rapid release of encapsulated drugs at targeted tumours or disease tissues. The successful completion of this project represents a significant advance on existing liposomal drug delivery systems because MS channels open and release the drug into or onto the target cell immediately following liposome binding. Liposomal drug delivery systems offer the additional advantages that they concentrate the drug inside the target tissue, thereby increasing its efficacy; reduce the exposure of healthy cells to toxic drugs; and increase safety to patients through loading site-specific drugs into site-directed liposomes. Specifically this project will develop: 1. Liposome formulations in which the MS channels are closed, but poised to open upon binding to the target cell. 2. Customised MS channels designed to optimize controlled release. 3. Structural information that will assist in the treatment of channelopathies linked to MS channels, i.e. diseases resulting from defects in MS ion channel function (e.g. muscular dystrophy, cardiac arrhythmias, autosomal-dominant polycystic kidney disease).Read moreRead less
Stimulus Induced Synaptic Plasticity In The Amygdala
Funder
National Health and Medical Research Council
Funding Amount
$428,777.00
Summary
Acute pain provides important warnings about dangers in our environment. However some clinical conditions produce chronic-persistent pain that outlasts the original injury and its useful role. This persistent pain is a debilitating condition that affects 20% of the Australian population and is characterized by painful sensory experience and a negative emotional state. The clinical management of persistent pain remains problematic due to the intolerable side effects associated with the escalating ....Acute pain provides important warnings about dangers in our environment. However some clinical conditions produce chronic-persistent pain that outlasts the original injury and its useful role. This persistent pain is a debilitating condition that affects 20% of the Australian population and is characterized by painful sensory experience and a negative emotional state. The clinical management of persistent pain remains problematic due to the intolerable side effects associated with the escalating doses required for adequate pain relief and the limited efficacy of current drug therapies in some clinically important pains states. The persistence of pain after the original injury has resolved suggest the development of adaptations that result in the ongoing pain. The changes in neurobiology underlying persistent pain are poorly defined. A better understanding of this neurobiology will result in better therapeutic approaches to persistent pain. The amygdala is a brain region that is important for pain processing, endogenous analgesia and emotion. A neuronal pathway that delivers information about pain to the amygdala has recently been shown to be critical for the development of persistent pain. Little is known about whether this critical neuronal pathway is modified by pain. This project will determine using electrical and chemical techniques how a brief or persistent painful stimulus changes the delivery of painful information to the neurons in the amygdala. The changes produced by a brief painful stimulus likely represent the initial changes in the development of a persistent pain state. This information may allow us to more fully understand the transition from acute to persistent pain and the changes defined may be sensitive to pharmacological modulation. Preventing or inhibiting these pain induced changes may provide better treatment for persistent pain or ideally prevent people undergoing the transition from acute to persistent pain.Read moreRead less