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Investigation Of Biological Ion Channels: Theoretical Formulation, Computer Simulation And Experimental Verification
Funder
National Health and Medical Research Council
Funding Amount
$677,292.00
Summary
All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, undertanding their mechanisms at a molecular level is a fundamental problem in neurobiology. There are many different types of ion channels, each type fulfilling a different role. For the first time, a group of American scientists have determined the shape of one type of ion channels. Using this newly unveiled information, we propose to build a mathematical theory of ion channels. And then, making ....All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, undertanding their mechanisms at a molecular level is a fundamental problem in neurobiology. There are many different types of ion channels, each type fulfilling a different role. For the first time, a group of American scientists have determined the shape of one type of ion channels. Using this newly unveiled information, we propose to build a mathematical theory of ion channels. And then, making use of a powerful supercomputer, we propose to follow the motion of ions as they move through the channel, study how a channel can select only the correct type of ions to traverse it and determine how many ions a single channel is capable of processing per second. The predictions made by our theory and computer simulations will be checked experimentally. If the predictions and experimental findings do not agree, we will modify the theory and make new predictions.Read moreRead less
Bacterial antibiotic resistance is mediated through specific biological molecules, so-called multidrug transporter proteins, which effectively export drugs from the cell. This proposal aims to solve the 3D structure of a multidrug resistance protein, NorM, which confers resistance to fluoroquinolone type drugs. Through this, we will provide detail into transport across the membrane of cells, and thus present a molecular understanding of bacterial antibiotic resistance.
Inactivation Of HERG Potassium Channels: Dynamic Changes In The Outer Pore Structure
Funder
National Health and Medical Research Council
Funding Amount
$422,716.00
Summary
Sudden cardiac death, due to disturbances in the normal electrical activity of the heart, is one of the leading causes of death in Australia and its incidence is increasing. Tackling the problem of cardiac arrhythmias is therefore one of the major challenges for cardiology in the 21st century. Two factors are greatly limiting progress in this area, the inability to predict who is most at risk and a paucity of treatment options. To address these problems, we need to better understand the basic me ....Sudden cardiac death, due to disturbances in the normal electrical activity of the heart, is one of the leading causes of death in Australia and its incidence is increasing. Tackling the problem of cardiac arrhythmias is therefore one of the major challenges for cardiology in the 21st century. Two factors are greatly limiting progress in this area, the inability to predict who is most at risk and a paucity of treatment options. To address these problems, we need to better understand the basic mechanisms underlying arrhythmias. The rhythm of the heart beat is controlled by electrical signals mediated by the flow of ions through specialised proteins called ion channels. Of the channels that contribute to cardiac electrical activity, potassium ion channels encoded by the Human ether-a-go-go-related gene (HERG) have been of particular interest for three reasons. Firstly, mutations in HERG are the cause of one third of cases of congenital long QT syndrome, an inherited cause of sudden cardiac death. Secondly, HERG is the molecular target for the vast majority of drugs that cause drug-induced long QT syndrome, the commonest cause of drug-induced arrhythmias and cardiac death. Thirdly, HERG channels have very unusual biophysical properties, which has led to the suggestion that they may act as an endogenous anti-arrhythmic agent . Accordingly, the major objective of the proposed research program is to understand the molecular and structural basis of the unusual properties of HERG channels. We will use a combination of molecular and electrical techiques in conjunction with computer modeling to probe the micoscopic motions in the channel that underly the unusual biophyscial properties of these channels. This work will facilitate a better understanding of how clinically identified mutations in HERG contribute to the increased risk of cardiac arrhythmias. More generally, it will improve our understanding of how cardiac ion channels maintain the normal rhythm of the heart.Read moreRead less
The rhythm of the normal heart beat is controlled by electrical signals mediated by the flow of ions. The movement of ions across heart cell membranes is predominantly mediated by ion channel proteins. One of these proteins, called HERG, has some very unusual properties that make it well suited for suppressing abnormal heart beats. We propose to undertake a detailed investigation of the mechanisms by which HERG channels open and close. The results will provided a greater understanding of how HER ....The rhythm of the normal heart beat is controlled by electrical signals mediated by the flow of ions. The movement of ions across heart cell membranes is predominantly mediated by ion channel proteins. One of these proteins, called HERG, has some very unusual properties that make it well suited for suppressing abnormal heart beats. We propose to undertake a detailed investigation of the mechanisms by which HERG channels open and close. The results will provided a greater understanding of how HERG channels work and how altered function of HERG channels in patients with heart disease leads to an increased risk of abnormal heart rhythms and sudden cardiac death.Read moreRead less
A rational approach to a high-resolution structure of the multidrug transporter EmrE. Membrane proteins form only 0.3% of the available protein structures in the protein data bank (PDB), yet 30% of the proteins in the human genome and 50% of human drug targets are membrane proteins. Multidrug transporters are membrane proteins responsible for antibiotic resistance in humans. A high-resolution structure of a multidrug resistance protein, together with comprehensive biochemical characterization, w ....A rational approach to a high-resolution structure of the multidrug transporter EmrE. Membrane proteins form only 0.3% of the available protein structures in the protein data bank (PDB), yet 30% of the proteins in the human genome and 50% of human drug targets are membrane proteins. Multidrug transporters are membrane proteins responsible for antibiotic resistance in humans. A high-resolution structure of a multidrug resistance protein, together with comprehensive biochemical characterization, would enable a detailed understanding of how these protein functions. Potentially it could also aid in the development of specific inhibitors that would prevent EmrE (and perhaps other similar proteins) from carry out its harmful mission. Read moreRead less
Mechanosensitive properties and modulation of N-methyl-D-aspartate (NMDA) receptors by lipid environment. This project will provide new information about the molecular determinants which influence NMDA receptor channel gating that will significantly advance our understanding of a link between NMDA receptor function and many neurodegenerative diseases as well as pain and learning and memory. The outcomes of this project may lead to the discovery of novel lipid-based biomaterials for application i ....Mechanosensitive properties and modulation of N-methyl-D-aspartate (NMDA) receptors by lipid environment. This project will provide new information about the molecular determinants which influence NMDA receptor channel gating that will significantly advance our understanding of a link between NMDA receptor function and many neurodegenerative diseases as well as pain and learning and memory. The outcomes of this project may lead to the discovery of novel lipid-based biomaterials for application in medicine and the drug industry. This research is highly significant in relation to human health. The biological and nutritional aspects of polyunsaturated lipids and dietary fish oils have long been recognized. Thus this project will provide further knowledge that could benefit the health of the nation with consequent reduced health care costs.Read moreRead less
Disorder as a novel determinant of photosynthetic structure and function: an experimental study. Australia enjoys a world reputation in photosynthesis research, typified by hosting the 2001 International Photosynthesis Congress. It also has a claim to fame for theoretical work in non-equilibrium thermodynamics concerning production of disorder or entropy, yielding new insights into planetary climates. This experimental project investigates the novel relation between entropy/entropy production ....Disorder as a novel determinant of photosynthetic structure and function: an experimental study. Australia enjoys a world reputation in photosynthesis research, typified by hosting the 2001 International Photosynthesis Congress. It also has a claim to fame for theoretical work in non-equilibrium thermodynamics concerning production of disorder or entropy, yielding new insights into planetary climates. This experimental project investigates the novel relation between entropy/entropy production and the structure/function of the solar powerhouse of plants (chloroplasts), and addresses fundamental questions at the interface of biology and physics. The research explores chloroplasts as a manifestation of the all-pervading Second Law of Thermodynamics, advancing Australia's contribution to basic science and helping to train researchers.Read moreRead less
Oxidative stress-induced alterations of the host erythrocyte by the malaria parasite. The malaria parasite spends part of its lifecycle inside the red blood cells of its host. During this time, the parasite modifies many of the features of the red blood cell and subjects it to high levels of oxidative stress. We will use and develop a variety of fluorescence and microscopic techniques to understand the molecular basis of the alterations in the organization of membrane proteins in malaria parasit ....Oxidative stress-induced alterations of the host erythrocyte by the malaria parasite. The malaria parasite spends part of its lifecycle inside the red blood cells of its host. During this time, the parasite modifies many of the features of the red blood cell and subjects it to high levels of oxidative stress. We will use and develop a variety of fluorescence and microscopic techniques to understand the molecular basis of the alterations in the organization of membrane proteins in malaria parasite-infected red blood cells. We will examine the roles of oxidative stress and of parasite proteins in modulating the properties of the host cell membrane.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0775613
Funder
Australian Research Council
Funding Amount
$467,000.00
Summary
Automated Patch Clamp System. Ion channels are membrane proteins that underlie cell function and are therefore important drug targets. The patch clamp technique is the most powerful tool available to study the function of single ion channels. The recent automation of this technology represents a quantum leap in our ability to perform high throughput screening of novel natural and synthetic compounds as drug leads. This will lead to an urgently needed increase in capacity, increasing the volume o ....Automated Patch Clamp System. Ion channels are membrane proteins that underlie cell function and are therefore important drug targets. The patch clamp technique is the most powerful tool available to study the function of single ion channels. The recent automation of this technology represents a quantum leap in our ability to perform high throughput screening of novel natural and synthetic compounds as drug leads. This will lead to an urgently needed increase in capacity, increasing the volume of research and its outcomes, which will benefit the Australian pharmaceutical industry and biosciences research community.
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Probing membrane rafts using surface-selective multi-dimensional microscopy. The results of this project will provide fundamental insights into the role played by domains in cell membranes in the regulation of membrane protein function. These insights will create new avenues in the biotechnology industry for development of novel therapeutics aimed at disruption of membrane protein-protein interactions that cause aberant cell signalling in disease states such as cancer.