Andrews Group - Systems Haematology

Systems Haematology Group
2016 group Back row L-R: Assoc/Prof Robert Andrews, Ms Amand Dharmaningputri, Front row L-R: Ms Jing Jing, Ms Shafira Rachmadi, Ms Fiona McCutcheon, Dr Elizabeth Gardiner, Absent: Dr Jane Arthur, Dr Ashwini Bennett, Ms Cheryl Berndt

Research Background

Platelets are part of the cardiovascular system and normally circulate in blood in a quiescent form. In response to tissue injury, platelets become activated and form a thrombus (blood clot) to block further loss of blood and begin the process of tissue repair. Under certain conditions of inflammation or disease, platelets can aberrantly be activated to form a thrombus. This type of unrestricted thrombus formation can lead to blockage of cerebral vessels (stroke) or coronary vessels (heart attack). In thrombosis, platelet adhesion and aggregation are initiated by engagement of specific membrane receptors that lead to platelet activation and integrin-dependent aggregation. At high shear stress, platelet adhesion is mediated primarily by binding of the platelet membrane glycoprotein (GP) Ib-IX-V complex to its ligand, von Willebrand Factor (VWF), and binding of GPVI to collagen. The binding of VWF to GPIb-IX-V is a critical event in initiating thrombosis. Distinct sites in the vWF A1 domain bind GPIb-IX-V, and leucine-rich repeats two through four of GPIb are involved in the binding of VWF. Signalling through GPIb-IX-V is dependent upon 14-3-3 zeta and the p85 subunit of PI 3-kinase, which bind to the alpha chain of GPIb. The cytosolic regulatory protein, calmodulin, also interacts directly with the cytoplasmic domains of both GPIb-IX-V and GPVI, associations that regulate the adhesive function and/or signal transduction mediated by these receptors. Activation of platelet signalling pathways leads to metalloproteinase-dependent shedding of platelet receptors, and is a key mechanism for regulation of platelet receptor levels and thus platelet function.

Current Projects

  • To identify the molecular determinants of VWF involved in recognition of platelet GPIb-IX-V, and how this interaction is regulated under shear conditions
  • To examine the pathophysiological significance of receptor shedding from activated platelets
  • To dissect the molecular interactions involved in 14-3-3 binding to PI3-kinase and to determine how 14-3-3 regulates the assemblage of GPIb-IX-V signalling complexes
  • To characterize the functional significance of the receptor/14-3-3/PI3-kinase complex in transfected cells and animal models
  • To analyze the function of calmodulin association with GPIb-IX-V and GPVI, and other ITAM-containing receptors in terms of ligand recognition, surface expression, cytoskeletal regulation or signalling
  • To characterize and analyze the production of reactive oxygen species in platelets in response to platelet activation induced by agonists or platelet adhesion
  • To examine the role of receptor-mediated platelet redox in Type I and Type II diabetes
  • To create and characterize new platelet function assays suitable for the analysis of blood samples from patients with thrombocytopenia (low platelet numbers in blood) and patients with acquired and congenital bleeding disorders

For current project opportunity descriptions please visit our honours page

Current Grants

  • National Health and Medical Research Council
  • National Heart Foundation funding
  • Monash University