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Blood platelet mechano-sensing of hyper-shear gradients at stenosis and mechanical circulatory support

Description 
Haematology Micro-platforms & Platelet & Thrombosis Laboratories. The Australian Centre for Blood Diseases. Haematology Micro-platforms & Platelet & Thrombosis Laboratories, Australian Centre for Blood Diseases (ACBD) have a collaborative program centred on the development and use of novel bioengineering approaches to investigate the mechano-biology of blood platelet function in the context of thrombosis and haemostasis. The research team for this project consists of Dr Warwick Nesbitt (ACBD), A/Prof Justin Hamilton (ACBD), and Prof Ivan Marusic (UoM). Background: Circulating platelets have evolved specialised adhesive and mechano-sensing mechanisms to promote efficient adhesion to regions of blood vessel damage and developing thrombi. The mechanisms regulating platelet adhesion under patho-physiological blood flow conditions have been primarily elucidated through the use of in vitro perfusion systems and animal models of thrombosis. These studies have demonstrated that platelets can form sustained adhesive interactions in response to shear gradients that are present at sites of arterial stenosis, within implantable medical devices such as LVAD, and within extracorporeal perfusion systems (ECMO). (1) In addition these studies have highlighted the acute sensitivity of platelets to micron-scale changes in the mechanical blood flow environment. Studies from our laboratories have demonstrated a key role for blood flow shear gradients in initiating pathological thrombus formation. (1) While it is well established that platelets become activated upon exposure to elevated blood shear forces through the engagement of several surface expressed adhesion receptors such as GP1b/V/IX and integrin aIIbb3, the way in which platelets sense and respond to changing shear stresses in bulk flow, in the absence of adhesion receptor engagement is poorly defined. In particular, the role that blood flow shear and elongational stress gradients play and the specific cell signalling mechanisms that allow platelets to sense such gradients, in the absence of adhesion receptor engagement in blood flow is unknown. Aims:This project will focus on delineating a novel mechano-sensing response of platelets to hyper-shear gradients found at acute stenosis and in implantable mechanical circulatory support devices. Methods: Through the course of this multidisciplinary project student(s), in conjunction with biologists and engineers within the Australian Centre for Blood Diseases and the University of Melbourne, will utilise novel microfluidic blood flow2,3 and cell trapping systems to investigate the cell signalling processes that enable platelets to sense their mechanical flow environment and the precise mechanical forces that effect platelet signalling function. Students will utilise a range of cell biological techniques including, FACS based cell assays, live cell epifluorescence and confocal microscopy, and Western blotting techniques to probe platelet mechano-signalling. In addition students will have the opportunity to work within a state of the art clean room facility (Micro nano Fabrication Research Facility; RMIT) where they will gain experience in microfluidic fabrication processes. Student(s) will apply these novel microfluidic and cell biology platforms to begin to investigate a role for members of the PI3 kinase enzyme family in modulating adhesion receptor independent platelet mechano-sensing. In addition, using microscopy and computational approaches students will investigate the precise mechanical forces that drive thrombosis in the context of heart attack and ischaemic stroke. Outcomes from this project will inform the future development of a novel class of anti-clotting drugs. Ideally students will have a keen interest in cell biology, and mechano-biology and have an interest in working at the interface between biomedical and bio-engineering disciplines. 1. A shear gradient-dependent platelet aggregation mechanism drives thrombus formation. Nat Med. 2009 Jun;15(6):665-73. 2. Application of a strain rate gradient microfluidic device to von Willebrand's disease screening. Lab Chip. 2017 Jul 25;17(15):2595-2608. 3. A microfluidics device to monitor platelet aggregation dynamics in response to strain rate micro-gradients in flowing blood. Lab Chip. 2010 Feb 7;10(3):291-302.
Essential criteria: 
Minimum entry requirements can be found here: https://www.monash.edu/admissions/entry-requirements/minimum
Keywords 
mechano-sensing blood platelets thrombosis cardiovascular disease microfluidics, physiology, pharmacology, anatomy, developmental biology, molecular biology, biochemistry, immunology, human pathology, clinical
School 
Central Clinical School » Australian Centre for Blood Diseases (ACBD)
Available options 
PhD/Doctorate
Masters by research
Honours
BMedSc(Hons)
Time commitment 
Full-time
Top-up scholarship funding available 
No
Physical location 
Alfred Research Alliance
Co-supervisors 
Assoc Prof 
Justin Hamilton
Prof 
Ivan Marusic
(External)

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