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 C-type Lectin, Mincle, Is A Macrophage Receptor For Candida Albicans.
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
The yeast Candida albicans is an important opportunistic infection that causes both mucosal and disseminated disease in patients whose innate or adaptive immune responses are impaired Infection and proliferation results in fungal colonisation of the tissues, and a variable degree of tissue damage. The latter is determined both by the virulence properties of the organism and by the genetic makeup of the host. This large, extracellular pathogen is eradicated from the body predominantly by acavenge ....The yeast Candida albicans is an important opportunistic infection that causes both mucosal and disseminated disease in patients whose innate or adaptive immune responses are impaired Infection and proliferation results in fungal colonisation of the tissues, and a variable degree of tissue damage. The latter is determined both by the virulence properties of the organism and by the genetic makeup of the host. This large, extracellular pathogen is eradicated from the body predominantly by acavenger (phagocytic) cells, which are also important in determining the severity of the associated tissue lesions. A phagocytic cell that is central to both innate and adaptive immune responses is the macrophage, which not only takes up and kills the yeast, but also is capable of of killing and digesting it, and presenting the components to cells of the adaptive immune system. This project is based on the postulate that the outcome and severity of infection is determined, at least in part, by the early functional response of the macrophage to the overall virulence properties of the yeast. The response is initiated by interactions with cell-surface receptors, and this study will show that a novel macrophage receptor, Mincle, is an important part of the innate immune response to fungal infections. We have shown that it is associated with differences in susceptibility to yeast infections in inbred mouse strains; it can discriminate between different isolates of the yeast; and it initiates the inflammatory signalling cascade. Our project will define the specific role of this receptor in fungal infection. The results will be important in understanding the basic biology of host resistance, and will offer new opportunities for therapeutic intervention by selectively blocking or modifying different activation pathways.Read moreRead less