Investigation Of Shear-sensitive Signalling Pathways In Human Platelets
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
Platelets are extremely important cells that control bleeding by sticking to injured blood vessels to form a blood clot. Excessive clotting can lead to fatal vascular events such as heart attacks and strokes. On the other hand, defects in blood clotting can result in life threatening bleeding problems. Platelets stick to the wall of a blood vessel when receptors on the surface of these cells interact with materials (ligands) that are exposed when the vessel wall is injured. The stickiness or adh ....Platelets are extremely important cells that control bleeding by sticking to injured blood vessels to form a blood clot. Excessive clotting can lead to fatal vascular events such as heart attacks and strokes. On the other hand, defects in blood clotting can result in life threatening bleeding problems. Platelets stick to the wall of a blood vessel when receptors on the surface of these cells interact with materials (ligands) that are exposed when the vessel wall is injured. The stickiness or adhesive behaviour of platelets is controlled by many proteins (enzymes) which are contained inside these cells. These enzymes transmit messages from platelet receptors on the surface into the cell interior, thereby controlling platelet behaviour. We are in the process of identifying several types of enzymes which are responsible for controlling platelet stickiness. Our research will provide a better understanding of the complicated pathways regulating platelet stickiness and clot formation. The knowledge gained from these studies may ultimately asssist in the design of specific drugs for the prevention and-or treatment of heart attacks and strokes.Read moreRead less
Novel Functional Domains On Adrenoceptors For Drug Interaction And Cell Signalling
Funder
National Health and Medical Research Council
Funding Amount
$801,500.00
Summary
Our work involves studying cell-surface proteins (receptors) that respond to hormones such as adrenaline or substances that transmit signals in the nervous system (neurotransmitters). These receptors play a vital role in orchestrating responses to stimuli such as stress, pain, changes in blood pressure, body temperature, fluid and energy status, and exercise. They allow communication between different organs or different parts of the nervous system. G-protein coupled receptors (GPCRs) are the ma ....Our work involves studying cell-surface proteins (receptors) that respond to hormones such as adrenaline or substances that transmit signals in the nervous system (neurotransmitters). These receptors play a vital role in orchestrating responses to stimuli such as stress, pain, changes in blood pressure, body temperature, fluid and energy status, and exercise. They allow communication between different organs or different parts of the nervous system. G-protein coupled receptors (GPCRs) are the major group of cell surface receptors that interact with hormones and neurotransmitters. Treatment of many diseases and conditions relies on the use of drugs that selectively activate or block a single type of GPCR. In fact, about 2-3 of existing therapies are based on these drugs. In designing new drugs it is important to understand as much as possible about the properties of the target receptors. There is emerging evidence concerning interactions between drugs, receptors and proteins inside cells that translate signals into responses (signalling proteins). For example, receptors have additional sites of drug action that can modulate their activity, and can also couple to multiple signalling pathways. We are studying adrenoceptors that respond to adrenaline and to the neurotransmitter noradrenaline. Our studies will use adrenoceptors as model systems to identify novel potential sites for drug interaction, to gain new insights into signalling mechanisms utilized by these receptors and to examine how a variety of phosphorylation mechanisms affect the ability of receptors to couple to particular signalling pathways.Read moreRead less
Investigation Of Negative Signalling Mechanisms In Platelets
Funder
National Health and Medical Research Council
Funding Amount
$292,500.00
Summary
Platelets are specialised blood cells essential for normal blood clotting. We are studying the processes that control platelets sticking to the exposed vessel wall, to each other and to other cells to form a stable blood clot at the site of injury to stop bleeding. The same processes, when unchecked, could lead to the formation of harmful large blood clots that may block blood vessels in the heart or brain, resulting in heart attack or stroke. Platelets stick to the blood vessel wall and each ot ....Platelets are specialised blood cells essential for normal blood clotting. We are studying the processes that control platelets sticking to the exposed vessel wall, to each other and to other cells to form a stable blood clot at the site of injury to stop bleeding. The same processes, when unchecked, could lead to the formation of harmful large blood clots that may block blood vessels in the heart or brain, resulting in heart attack or stroke. Platelets stick to the blood vessel wall and each other through sticky proteins called receptors on the cell surface. Receptors are able to bind to their specific ligands such as von Willebrand factor (vWf) and collagen which become exposed following vessel wall damage. The interaction between the ligands and receptors will trigger many biochemical changes within platelets, called signal transduction, that control platelet stickiness. The aim of this research project is to investigate the signalling processes that are utilised by the major platelet receptor called integrin alpha IIb beta 3. We are particularly interested in identifying the negative signalling process utilised by this receptor to dampen the positive signals required for platelet stickiness, to achieve a balanced clotting process. The identification of these specific signalling pathways will not only increase our knowledge of blood clot formation in health and disease, but also help develop potential new therapies for the prevention of heart diseases and strokes.Read moreRead less
Investigation Of The Mechanisms Involved In Consolidation Of Memory By Beta 3 Adrenoceptoragonists.
Funder
National Health and Medical Research Council
Funding Amount
$241,018.00
Summary
The inability to form new memories is a major and increasingly prevalent health problem for an aging population. In addition to aging, the inability to form new memories is associated with serious medical conditions including Alzheimer's Disease and diabetes. Common to these conditions is the inability to consolidate memories. Memories are intact for a short while (30 minutes) after the event to be remembered, but memory does not pass on into permanent storage. We have been able to achieve memor ....The inability to form new memories is a major and increasingly prevalent health problem for an aging population. In addition to aging, the inability to form new memories is associated with serious medical conditions including Alzheimer's Disease and diabetes. Common to these conditions is the inability to consolidate memories. Memories are intact for a short while (30 minutes) after the event to be remembered, but memory does not pass on into permanent storage. We have been able to achieve memory consolidation in a particular learning task, which is not normally remembered, by injection of drugs acting on novel receptors (beta 3 adrenoceptors) in the brain of day old chicks. These drugs mimic the action of noradrenaline at beta-3 adrenoceptors. There are a number of ways in which memory consolidation can be enhanced, and we will compare the effects of beta-3 drugs with other potential drugs acting at other types of noradrenaline receptors. One of the actions of beta-3 agonists is related to the uptake of glucose into cells in the brain. We will investigate whether the mechanism of beta-3 enhancement of memory involves the uptake of glucose in brain tissue and studies in cultures of individual cell types will show us which cells are involved. Although this work is done using young chicks, there is no reason to suppose that the basic memory mechanisms at the level of the nerve cell should be different in birds or mammals. There are distinct advantages to using chicks in this research as they can form a long lasting memory for an experience lasting only 10 seconds, and they will discriminate between different colours as part of their learning. This research is aimed at understanding the processes involved in and influencing memory formation. If we are going to develop drugs to alleviate the cognitive problems of old age and more serious cognitive diseases, we need to understand more about the basic mechanisms of memory formation in the normal animal.Read moreRead less
Dissecting The Role Of The IL-3 Receptor Alpha Subunit And Beta-catenin In Acute Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$583,312.00
Summary
Leukaemia is a devastating form of blood cancer affecting both young and old. We aim to understand the mechanisms of uncontrolled cell growth associated with acute myeloid leukaemia. We focus on the role of key growth regulators that are abnormally active in the critical leukaemia stem cells. Understanding the biological and molecular properties of these cells is of considerable importance for development of the next generation of leukaemia therapies.
Discovery Of A Novel Immune Evasion Strategy Employed By Mosquito Borne Viruses To Suppress Antiviral Immune Responses
Funder
National Health and Medical Research Council
Funding Amount
$418,642.00
Summary
The transition from mosquitoes, ticks, or other invertebrate vectors to the human hosts represents a crucial step in the successful establishment of arthropod borne viruses (arboviruses). The incidence of arbovirus infections such as dengue virus, West Nile virus, Ross River virus is increasing at an alarming rate in various parts of the world. In addition, the emergence of new viruses resulting in significant mortality in the population is of utmost concern. Vaccines for many of these viruses r ....The transition from mosquitoes, ticks, or other invertebrate vectors to the human hosts represents a crucial step in the successful establishment of arthropod borne viruses (arboviruses). The incidence of arbovirus infections such as dengue virus, West Nile virus, Ross River virus is increasing at an alarming rate in various parts of the world. In addition, the emergence of new viruses resulting in significant mortality in the population is of utmost concern. Vaccines for many of these viruses remain elusive. One factor that contributes to this is the ability of viruses to develop ingenious strategies to avoid or suppress the host defence systems, which enable its successful establishment in the host. Understanding how viruses evade-suppress host defence machinery will certainly enhance and improve our approaches to fight them. For the first time internationally we have discovered a new and novel pathway employed by arboviruses to suppress antiviral immune responses in the host. We have discovered that naturally occurring carbohydrates on viruses derived from mosquito cells, would influence these virus s ability to evade-suppress host antiviral proteins such as interferons. This may be a general effect of arboviruses or may even extend to other viruses , which include a number of deadly pathogens (HIV, Influenza). This research has the potential to significantly expand our understanding of how these viruses establish infection and cause disease. Also this discovery has broader implications for understanding inflammatory processes and their regulation.Read moreRead less
Viral Targeting Of STAT Proteins: Roles In Disease
Funder
National Health and Medical Research Council
Funding Amount
$536,985.00
Summary
The capacity of viruses to evade the host immune response is critical to the development of disease. We recently showed that interaction of specific viral proteins with host immune proteins called STATs is vital to lethal disease caused by lyssaviruses. In this project, we aim to define in detail the functions of these interactions in viral modification of host biology and evasion of the immune response, and to use this information to develop new vaccines against highly pathogenic human viruses.