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
Determining The Cellular Mechanisms Involved In The Airway Response To Topical Citrate
Funder
National Health and Medical Research Council
Funding Amount
$444,491.00
Summary
The air passages of the lungs are lined by mucous membranes. These membranes are covered by a thin layer of fluid to protect the airways from drying. This fluid allows the cilia, the hair like projections on top of the airway cells to beat more effectively to remove mucous and inhaled particles from the lungs. The volume and composition of this fluid is determined by the salt and water movement across the mucous membranes of the airways. These processes are abnormal in cystic fibrosis (CF), the ....The air passages of the lungs are lined by mucous membranes. These membranes are covered by a thin layer of fluid to protect the airways from drying. This fluid allows the cilia, the hair like projections on top of the airway cells to beat more effectively to remove mucous and inhaled particles from the lungs. The volume and composition of this fluid is determined by the salt and water movement across the mucous membranes of the airways. These processes are abnormal in cystic fibrosis (CF), the most common lethal inherited disease affecting Australians. In CF, an abnormal gene disrupts one of the major mechanisms for salt and water movement in the air passages. This abnormal salt transport causes drying of the airway surface which impairs the working of the cilia. This leads to retention of mucous in the airways with repeated bacterial infections damaging the lungs. Over the last 10 years, we have developed a series of simple tests to measure the abnormalities in the CF airway of human subjects. We have isolated an exciting new clinical application for sodium citrate, a substance used in blood transfusions. Citrate appears to alter both the salt transport abnormalities found in CF. This research proposal seeks to better understand the dual effects of citrate and to test similar compounds that may have stronger effects. The ultimate aim of our research is to have sufficient knowledge to work out the best way to develop a new treatment for CF.Read moreRead less
Molecular Determinants Of Inhibitory Synaptic Function Studied Using Mutant And Transgenic Mice
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Communication between nerve cells is the key to effective brain function and when disturbed, pathological states such as epilepsy, schizophrenia, fear and anxiety, spasticity and motor disorders ensue. This project is based on new data which suggests that the site of this communication, called the synapse, is a much more dynamic structure than previously thought. Based on our work to date, where we have demonstrated the recruitment of selected classes of neurotransmitter receptors into synapses, ....Communication between nerve cells is the key to effective brain function and when disturbed, pathological states such as epilepsy, schizophrenia, fear and anxiety, spasticity and motor disorders ensue. This project is based on new data which suggests that the site of this communication, called the synapse, is a much more dynamic structure than previously thought. Based on our work to date, where we have demonstrated the recruitment of selected classes of neurotransmitter receptors into synapses, our aim is to use a range of naturally occuring mice mutants, as well as transgenic mice to modulate the receptor levels and so to examine the role of synaptic function and synaptic dynamics. The outcomes of this project will provide fundamental new knnowledge aimed at understanding how communication in the nervous system works and may suggest ways in which modulation of this information flow could be used to treat disorders of brain function.Read moreRead less
Theoretical Investigations Into Permeation Dynamics In Calcium- And Potassium-Selective Membrane Ion Channels
Funder
National Health and Medical Research Council
Funding Amount
$517,243.00
Summary
All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, understanding their mechanisms at a molecular level is a fundamental problem in biology. There are many different types of ion channels, each type fulfilling a different role. We now know the exact atomic structures of several types of the proteins forming ion channels. Using this newly unveiled information, we propose to build exact physical models of two important classes of ion channels, namely, ....All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, understanding their mechanisms at a molecular level is a fundamental problem in biology. There are many different types of ion channels, each type fulfilling a different role. We now know the exact atomic structures of several types of the proteins forming ion channels. Using this newly unveiled information, we propose to build exact physical models of two important classes of ion channels, namely, the calcium channels and potassium channels, using the technique known as 'homology' modelling. Then, making use of powerful supercomputers and the special computer programs we have devised, we propose to follow the motion of ions as they move through the channel and study how some chemical compounds or drugs interfere with the normal functioning of the channel. Specifically, we will attempt to understand how verapamil, which is used to treat irregular heart beats and high blood pressure, interact with the calcium channel. Once we fully understand how these channels work, we will be able to understand the causes of, and possibly find the cures for, many neurological and muscular disorders, such as cardiac arhythmia and hypertension.Read moreRead less
Interactions Between H5N1 And The Respiratory Epithelium
Funder
National Health and Medical Research Council
Funding Amount
$623,065.00
Summary
This project examines the hypothesis that the severity of H5N1 infection is due to activation of signalling pathways in the lung not activated by human influenza and leads to fluid accumulation in the lungs death of respiratory cells. This study will improve our understanding of influenza infection and identify targets for treatment of H5N1.
Effects Of Pharmacological Modification Of Ion Channel Activity On The Excitability Of Normal And Diabetic Nerves.
Funder
National Health and Medical Research Council
Funding Amount
$389,232.00
Summary
Neuropathic disturbances due to diabetes can destroy the quality of life and place a major cost burden on society. This project will provide insight into the actions of specific pharmaceutical agents on human nerves in both healthy subjects and diabetic patients with a view to establishing how these drugs reduce neuropathic symptoms in real life. The study will provide information regarding the underlying causes of neuropathic symptoms in diabetes and may help guide future treatments.