Investigating The Link Between Oxidative Stress And Biomechanical Integrin Activation In Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$653,742.00
Summary
Diabetes represents a serious healthcare problem globally. A large proportion of deaths associated with diabetes can be attributed to the development of blood clots in the circulation of the heart and brain (heart attack/stroke). The blood clotting mechanism is ‘hyperactive’ in diabetes, although the reason for this is not well defined. In this proposal we will investigate a new mechanism promoting blood clots, and will investigate innovative approaches to reduce this clotting mechanism.
Regulation Of Receptors That Control Platelet Function Under Shear Stress
Funder
National Health and Medical Research Council
Funding Amount
$507,273.00
Summary
Specialized human blood cells that control blood loss and clotting (platelets) are currently difficult to test in the clinical laboratory, meaning patients are at risk of excessive bleeding or serious clot formation during disease or treatment. The aim of this proposal is to use our new reagents and assays to develop more reliable methods for evaluating relative bleeding or clotting risk in individuals.
Ligand Interactions Of Platelet Glycoprotein Ib-IX-V In Thrombosis
Funder
National Health and Medical Research Council
Funding Amount
$363,098.00
Summary
The transition of circulating blood platelets from a fluid-phase, non-adherent state to an adherent, activated and aggregated state (thrombus formation) is critical in the normal haemostatic response to blood vessel injury and in thrombotic diseases such as heart attack and stroke. One unique platelet receptor, the glycoprotein Ib-IX-V complex, is of particular interest, because it initiates platelet aggregate or thrombus formation at high fluid shear stress in flowing blood, including the patho ....The transition of circulating blood platelets from a fluid-phase, non-adherent state to an adherent, activated and aggregated state (thrombus formation) is critical in the normal haemostatic response to blood vessel injury and in thrombotic diseases such as heart attack and stroke. One unique platelet receptor, the glycoprotein Ib-IX-V complex, is of particular interest, because it initiates platelet aggregate or thrombus formation at high fluid shear stress in flowing blood, including the pathological shear stress that occurs in a sclerotic coronary artery. Our published and preliminary results show how GPIb-dependent interaction of platelets with von Willebrand factor, the major adhesive ligand for GPIb-IX-V, is dependent on the level of shear stress. Using a cross-species (human to canine) homology-swap approach, where human sequence is replaced by the corresponding canine sequence within discrete structural domains, a sequence of GPIb has been identified which becomes increasingly important as hydrodynamic shear stress increases. It is proposed to further define the interactive surface of GPIb that recognizes von Willebrand factor at increasing shear, and to define the relationship between the shear-dependent alteration of GPIb conformation and its ability to interact with other pro-thrombotic or pro-inflammatory binding partners.Read moreRead less
The Role Of The Platelet Glycoprotein Ib Alpha Cytoplasmic Domain In Thrombosis
Funder
National Health and Medical Research Council
Funding Amount
$600,230.00
Summary
Our studies aim to provide a better understanding of the factors that make platelets sticky, because this is important not only for normal blood clot formation but also in the development of harmful blood clots (thrombosis). Improving our understanding of these processes will add significantly to our knowledge of how blood clotting is controlled. This information is relevant to many human diseases including heart attack and stroke and will help us to develop drugs to prevent these diseases.
Investigation Into The Intervention Of Arterial Thrombosis And Atherosclerosis Using Shear Sensitive Nanoparticle Drug Delivery
Funder
National Health and Medical Research Council
Funding Amount
$462,601.00
Summary
In this project we aim to provide a targeted therapy that inhibits atherosclerosis, in-stent restenosis and thrombosis; pathologies characterized by high shear stress due to a reduction in the vessel lumen. We will apply microfluidic technology to characterize lipid nano-capsules that are tagged with antibodies against activated platelets or VCAM-1, loaded with anti-platelet or immune suppressive drugs and are prone to rupture specifically under high shear stress conditions.
Blood clotting is the underlying cause of heart attacks and strokes. We have discovered that the protein, ERp5, is essential for normal blood clotting. Our preliminary findings indicate that ERp5 controls the function of blood platelets in clotting. Our overall aim is to elucidate how ERp5 regulates platelet function. It is crucial that we understand how ERp5 functions in blood clotting if we are to effectively target it in disease.
Microfluidic Device Fo The Quantitative Assessment Of Blood Platelet Aggregation Behaviour
Funder
National Health and Medical Research Council
Funding Amount
$270,114.00
Summary
This project will develop a low-cost microfluidic chip which utilises dynamic shear stress to assess the propensity of blood clotting. This tool will analyze a tiny sample of blood and will predict excessive or ineffective clotting. The project will develop the chip and a low-cost 'chip reader' such that the tool can be operated at the point of care with only basic training.
Investigation Of Activating Signals Transmitted During Platelet Aggregation
Funder
National Health and Medical Research Council
Funding Amount
$267,750.00
Summary
The blood platelet is a specialized adhesive cell that plays a critical role in the normal blood clotting process through its ability to rapidly adhere to sites of vascular damage. Upon injury to a blood vessel, platelets undergo a number of internal signalling process and strucural changes that allow them to rapidly adhere to the area of damage. Following this initial adhesion process, platelet-platelet interactions occur leading to the development of a stable blood clot. Our research studies a ....The blood platelet is a specialized adhesive cell that plays a critical role in the normal blood clotting process through its ability to rapidly adhere to sites of vascular damage. Upon injury to a blood vessel, platelets undergo a number of internal signalling process and strucural changes that allow them to rapidly adhere to the area of damage. Following this initial adhesion process, platelet-platelet interactions occur leading to the development of a stable blood clot. Our research studies are aimed at understanding more closely the factors that regulate platelet-platelet interactions during the course of blood clot formation, since this is an important determinant not only of normal clot formation, but also in the development of harmful blood clots (thrombi) associated with the onset of diseases such as heart attack and stroke. Our particular focus is on the way in which platelets communicate to one another during the course of platelet thrombus development. Particulary, we are interested in the role of calcium as a signal mediating platelet-platelet communication. We believe that the transmission of these calcium signals may be the key signaling mediator of blood clot formation and normal haemostasis.Read moreRead less