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Role Of Indoleamine 2,3-dioxygenase In Vascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$271,500.00
Summary
Atherosclerosis and its clinical presentation including heart attack and stroke represent a major source of morbidity and mortality in the developed world, including Australia. Atherosclerosis involves the accumulation of lipid-laden cells in the wall of arteries that generates plaques resulting in a decrease in the lumen of the affected vessel that can impede or block blood flow resulting in clinical complications. The cellular events involved in atherosclerosis are complex. However, increasing ....Atherosclerosis and its clinical presentation including heart attack and stroke represent a major source of morbidity and mortality in the developed world, including Australia. Atherosclerosis involves the accumulation of lipid-laden cells in the wall of arteries that generates plaques resulting in a decrease in the lumen of the affected vessel that can impede or block blood flow resulting in clinical complications. The cellular events involved in atherosclerosis are complex. However, increasing information indicates that atherosclerosis involves an inappropriate response of the immune and inflammatory systems. This proposal plans to investigate the role of a protein, indoleamine 2,3-dioxygenase (IDO) that is increased during inflammation and is important for the regulation of the host's immune system. We propose that increasing IDO activity in inflammatory cells will attenuate the degree of vascular disease by decreasing the overall level of immune activation and inflammation in the blood vessels. We will test this by modulating the expression and activity of this protein in animal models of vascular disease, measure the extent of disease and then elucidate the mechanisms by which the protein acts. The significance of these studies is that they will provide useful information on the inflammatory and immune processes involved in the progression of atherosclerosis and may identify a potential novel target for therapeutic intervention.Read moreRead less
Bifunctionalised Contrast Nanoparticles For Simultaneous Diagnosis And Treatment Of Thrombosis, Vulnerable Plaques And Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$412,882.00
Summary
The aim of this project is to develop bifunctionalised contrast nanoparticles which selectively target molecular markers of cardiovascular and inflammatory diseases at various states. The nanoparticles would provide an advanced imaging technique for early diagnosis of fatty tissue build up in the vessel wall and for detecting vessel blockages. The nanoparticles would also work as drug carrier that specifically brings curative drugs to the disease site for an acute treatment simultaneously with d ....The aim of this project is to develop bifunctionalised contrast nanoparticles which selectively target molecular markers of cardiovascular and inflammatory diseases at various states. The nanoparticles would provide an advanced imaging technique for early diagnosis of fatty tissue build up in the vessel wall and for detecting vessel blockages. The nanoparticles would also work as drug carrier that specifically brings curative drugs to the disease site for an acute treatment simultaneously with diagnosis.Read moreRead less
Novel 18F And 64Cu Labelled Targeted Nanoparticles For Molecular Positron Emission Tomography: A Means For Early And Sensitive Detection Of Thrombosis, Inflammation And Vulnerable, Rupture-prone Atherosclerotic Plaques
Funder
National Health and Medical Research Council
Funding Amount
$572,931.00
Summary
The aim of this project is to develop novel targeted positron emission tomography imaging agents that seek out specific markers for various states of cardiovascular disease. These agents would provide a method for detecting the presence and level of atherosclerosis and thrombotic events. The targeted nanoparticles may provide a unique opportunity to detect very early plaques and the vulnerability of existing plaques.
Probing The Control And Action Of CLIC1/NCC27, An Unusual Chloride Ion Channel, By X-ray Crystallography
Funder
National Health and Medical Research Council
Funding Amount
$271,320.00
Summary
Cells must regulate the flow of ions and water across their membranes in order to survive and function normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first to identify and characterise a new class of chloride channel wh ....Cells must regulate the flow of ions and water across their membranes in order to survive and function normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first to identify and characterise a new class of chloride channel which plays a key roles in the regulation of the immune system. These channels are unusual in that they can move between two states: a soluble state and a state that resides in the cell membrane. We have determined the first structure of this class of channel in the soluble state. In this project, we will determine: how the protein makes the transition into the membrane state; which factors control this transition; and the structure of the protein in the membrane state. We will also determine how several drugs control the activity of this channel. The results of our work will have specific implications for our channel and will serve as a paradigm for other members of this new class of chloride channel. Understanding how this channel functions and how the current drugs control it will lead to the development of a new class of therapeutic agents that will control these channels by preventing the transition from the soluble to the membrane state.Read moreRead less
Cells must regulate the flow of ions and water across their membranes in order to survive and function normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first to identify and characterise a new class of chloride channel wh ....Cells must regulate the flow of ions and water across their membranes in order to survive and function normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first to identify and characterise a new class of chloride channel which plays a key roles in the regulation of the immune system. These channels are unusual in that they can move between two states: a soluble state and a state that resides in the cell membrane. We have determined the first structures of this class of channel in both the soluble state and what is believed to be the membrane docking state. This has given us the first atomic picture of how this channel protein can alter its structure so as to carry out its function. In this project, we will determine: how the protein completes the transition into the membrane state; the structures of other key members of this class of channel protein; complexes between channel proteins and other cellular proteins; and the structure of the protein in the membrane state. We will also determine how several drugs control the activity of this channel. The results of our work will have specific implications for our channel and will serve as a paradigm other members of this new class of chloride channel. Understanding how this channel functions and how the current drugs control it will lead to the development of a new class of therapeutic agents that will control these channels by preventing the transition from the soluble to the membrane state.Read moreRead less
Regulation Of Synthesis, Dimerisation And Secretion Of The Amyloidogenic Protease Inhibitor Cystatin C
Funder
National Health and Medical Research Council
Funding Amount
$423,565.00
Summary
The cells that compose our tissues are embedded in a complex mesh of extracellular proteins (for example collagen) that provide support, strenght and elasticity to the tissues. This extracellular matrix is not static; it is constantly remodelled when, for example, the cells of the immune system move through interstitial spaces to monitor the healthiness of the tissues. When infections or injuries occur, the inflammatory reactions that develop, and the processes involved in tissue repair, also in ....The cells that compose our tissues are embedded in a complex mesh of extracellular proteins (for example collagen) that provide support, strenght and elasticity to the tissues. This extracellular matrix is not static; it is constantly remodelled when, for example, the cells of the immune system move through interstitial spaces to monitor the healthiness of the tissues. When infections or injuries occur, the inflammatory reactions that develop, and the processes involved in tissue repair, also involve profound changes in the composition of the extracellular matrix. Such processes are also important for tumour growth; the cancer cells need to clear their way through interstitial space to escape to circulation and metastasize. During all these processes, the cells release to the extracellular space proteases that degrade collagen and the other components of the extracellular matrix. Obviously, these proteases must be tightly regulated to prevent them running out of control, so the cells also produce inhibitors of the proteases. The amount of proteases and inhibitors contained in the extracellular space must be maintained properly. If this equilibrium is disrupted, this can lead to pathology For instance, atherosclerosis is caused in part by excessive proteolysis of the blood vessel wall. In this project we want to study the mechanisms of one of the most abundant and important inhibitors of extracellular proteolysis: Cystatin C. We have discovered that certain cells of the immune system called dendritic cells posses interesting mechanisms to regulate how much Cystatin C they secrete. Furthermore, one of this mechanisms, which consists of pairing the protein to produce inactive dimers, may be the cause of some diseases characterised by accumulation of Cystatin C in the extracellular space. Our study may allow us to design therapies for the treatment of pathologies associated with defective or excessive production of Cystatin C.Read moreRead less
The Structure - Function Relationship Of NCC27, A Novel Nuclear Chloride Ion Channel Protein
Funder
National Health and Medical Research Council
Funding Amount
$241,527.00
Summary
Ion channels (IC) are complex proteins that regulate the transport of salts, an essential cell function. We have recently cloned a new IC, NCC27, unique in its location on the nuclear membrane, a site where they were previously thought to be unnecessary. The function of nuclear membrane ICs is unknown but our studies suggest that NCC27 is involved in regulating cell division. Because NCC27 has unique functional and structural characteristics, it will be particularly useful for answering fundamen ....Ion channels (IC) are complex proteins that regulate the transport of salts, an essential cell function. We have recently cloned a new IC, NCC27, unique in its location on the nuclear membrane, a site where they were previously thought to be unnecessary. The function of nuclear membrane ICs is unknown but our studies suggest that NCC27 is involved in regulating cell division. Because NCC27 has unique functional and structural characteristics, it will be particularly useful for answering fundamental questions relevant to the biology of animal cells: the role of nuclear membrane ICs in cell division; the way the structure of NCC27 allows it to carry out its function.Read moreRead less
Novel Mechanisms In Regulating Cytokine Secretion In The Inflammatory Response
Funder
National Health and Medical Research Council
Funding Amount
$323,160.00
Summary
Macrophages are key cells in the immune and inflammatory response. They play a role in many biological processes including wound healing and resistance to tumours and infections. It is also a major cell involved in mediating inflammation and tissue damage in chronic inflammatory diseases such as atherosclerosis and rheumatoid arthritis. The macrophage's role in these processes is achieved in large part by secreting enzymes and other proteins called cytokines to the outside of the cell. These cyt ....Macrophages are key cells in the immune and inflammatory response. They play a role in many biological processes including wound healing and resistance to tumours and infections. It is also a major cell involved in mediating inflammation and tissue damage in chronic inflammatory diseases such as atherosclerosis and rheumatoid arthritis. The macrophage's role in these processes is achieved in large part by secreting enzymes and other proteins called cytokines to the outside of the cell. These cytokines are synthesized by the macrophage and travel through a secretory pathway in the cell, in order to be released to the outside of the cell. There are various quality control mechanisms along the pathway which ensure only correctly made functional protein is secreted out of the cell. One cytokine, called macrophage inhibitory cytokine is produced by the immune cells called macrophages only when they become activated to mount an immune response against invading pathogens. The cell uses a novel mechanism to ensure the quality control of this cytokine. The propeptide of this cytokine targets incorrectly folded cytokine to a protein complex called the proteasome for degradation. This prevents secretion of inactive cytokine. Additionally, the propeptide of the cytokine helps secretion from macrophages by a novel mechanism. Because of these characteristics the cytokine provides a good model to study secretion from macrophages under pro- and anti-inflammatory conditions. In addition, demonstrating that activation of the macrophages causes a major upregulation in the synthesis and secretion of cytokines by novel mechanisms, will further our understanding of how the macrophage operates in fulfilling its role in the immune response.Read moreRead less