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
A Novel Patch-fluorimetry Technique For Investigating Structural Changes During Gating Of Mechanosensitive Ion Channnels
Funder
National Health and Medical Research Council
Funding Amount
$387,018.00
Summary
Membrane proteins, especially membrane channels play an important role in regulating the flow of substances across the cell. Dysfunction in these channels can lead to a variety of diseases. Thus approximately 60% of drug development is targeted against such proteins. In our research, we are looking at membrane channels found in bacteria. Understanding the function of these channels will help us develop novel anti-bacterial agents. It will also aid to understand a role of ion channels in disease.
Theoretical Studies On The Dynamics Of Ion Permeation Across Membrane Channels
Funder
National Health and Medical Research Council
Funding Amount
$381,000.00
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 many different types of ion channels. Then, ma ....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 many different types of ion channels. Then, making use of powerful supercomputers, 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. 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, muscular and renal disorders.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
Computational Study Of Selectivity, Gating And Mutation In The Acetylcholine Receptor And Potassium Channels
Funder
National Health and Medical Research Council
Funding Amount
$301,393.00
Summary
One way cells in living organisms communicate with each other is via the passage of charged particles across the cell membrane. This takes place through ion channels, large protein molecules that span the membrane and allow small molecules or ions to pass through a central pore. Malfunction of ion channels is known to underlie a variety of disorders including epilepsy, hypertension, kidney disease, heart attack, deafness. Channels also provide promising targets for making new broad spectrum anti ....One way cells in living organisms communicate with each other is via the passage of charged particles across the cell membrane. This takes place through ion channels, large protein molecules that span the membrane and allow small molecules or ions to pass through a central pore. Malfunction of ion channels is known to underlie a variety of disorders including epilepsy, hypertension, kidney disease, heart attack, deafness. Channels also provide promising targets for making new broad spectrum antibiotics and antivirals. This project aims to study two important types of ion channel: acetylcholine receptors that convey signals between nerve and muscle cells, and potassium channels that regulate the nerve impulses themselves. The binding of the neurotransmitter acetylcholine released from a nerve cell to acetylcholine receptors in the muscle cell prompts the opening of a cation conductive pore. The resulting influx of ions initiates a cascade of events ending in the contraction of the muscle fibre. However, the way in which this channel opening is initiated and how ions move into the muscle cell remain to be determined. Potassium channels are primarily used to rapidly 'switch off' nerve impulses so that subsequent messages can be passed through the nerve cell. To do this they have to be highly discriminatory, allowing only potassium to pass across the cell membrane and not sodium that would initiate another impulse. Although we now know what these tiny proteins look like, it is not clear how they differentiate between types of ions while still allowing many millions to pass each second. We will use computer simulations to study how these two type of channel open and close, and how they discriminate between different ion types. Using sophisticated computational techniques on Australia's most powerful supercomputers we aim to elucidate this fundamental area of human biology in the hope of deriving treatments for some debilitating neuromuscular diseases.Read moreRead less
The Structural Basis For The Control Of Cardiac And Skeletal Muscle By The Troponin Complex
Funder
National Health and Medical Research Council
Funding Amount
$369,003.00
Summary
Many key physiological processes are controlled by large, multi-protein complexes. These molecular machines ensure that signals transmitted in the body are correctly interpreted and amplified so as to control key body functions. The Troponin protein complex is one such large multi-protein complex which is the switch used to control both heart and skeletal muscle contraction in the body. The Troponin complex responds to increasing cellular calcium levels, switching the muscle on at high calcium. ....Many key physiological processes are controlled by large, multi-protein complexes. These molecular machines ensure that signals transmitted in the body are correctly interpreted and amplified so as to control key body functions. The Troponin protein complex is one such large multi-protein complex which is the switch used to control both heart and skeletal muscle contraction in the body. The Troponin complex responds to increasing cellular calcium levels, switching the muscle on at high calcium. When calcium returns to its normal basal level, the Troponin complex switches the muscle off. Naturally occurring genetic errors can lead to the malfunction of the Troponin complex. This, in turn, can lead to severe and possibly fatal diseases of the heart and muscle systems. To gain an understanding of these molecular diseases, it is important to understand the structure, dynamics and function of the Troponin complex. This project will use a newly-developed magnetic resonance method to monitor changes in the Troponin structure as a function of calcium level. Each component of the Troponin complex will be labeled with magnetic tags, allowing the determination of both structure and dynamics of Troponin, both in solution and in active muscle fibres. The study will result in a molecular understanding of how the Troponin switch works. This will give great insight in how mutations result in cardiac and muscular diseases.Read moreRead less
The Dynamics Of Gradient Sensing By Growth Cones: Timelapse Imaging And Mathematical Modelling
Funder
National Health and Medical Research Council
Funding Amount
$493,305.00
Summary
Problems in the wiring up of the brain underlie several nervous system disorders. The goal of this project is to understand better how this wiring normally forms. This will ultimately lead to a better understanding of what can go wrong with brain wiring, and how to fix such problems. It will also lead to a better understanding of how to make axons regenerate after injury. Our approach is to use a combination of timelapse imaging of neurons in culture, and mathematical modelling, to understand ho ....Problems in the wiring up of the brain underlie several nervous system disorders. The goal of this project is to understand better how this wiring normally forms. This will ultimately lead to a better understanding of what can go wrong with brain wiring, and how to fix such problems. It will also lead to a better understanding of how to make axons regenerate after injury. Our approach is to use a combination of timelapse imaging of neurons in culture, and mathematical modelling, to understand how the tips of the wires growing between neurons sense their environment. By comparing our experimental measurements with our theoretical results we will arrive at a detailed and accurate model of this sensing process. This will allow us to make predictions about how these developmental events normally occur in vivo, and what can go wrong.Read moreRead less