Develop single-cell mechanobiological methods for discovering molecular mechanisms of cardiovascular and neuronal mechanical force sensing

Summary

We are developing cutting-edge technologies for the following biomedical application: 1) define the mechanosensing functions of key protein players in the cardiovascular system such as integrin receptors and mechanosensitive ion channels, and elucidate their contributions to the cardiovascular diseases - particularly thrombosis and guide the development of new anti-thrombotic therapeutic strategies; 2) investigate the transmembrane conduction of mechanical forces in neurology. In particular, the generation and regulation of force signals during membrane fusion such as the formation and regulation of SNARE complexes during neurotransmitter release. This study will provide fundamental biological insights for ongoing sensory bionics and implantable neuroprosthesis research.

Supervisor(s)

Dr Lining (Arnold) Ju

Research Location

Biomedical Engineering - BMIT, School of Physics, Brain and Mind Centre

Program Type

Masters/PHD

Synopsis

In view of the high complexity and dynamics of protein complexes that perform important physiological functions, it is difficult to visualise and characterise their kinetic and signaling processes on single living cells using traditional biochemical and biophysical techniques. It is therefore urgent to develop high-resolution bioimaging and single-molecule manipulation technologies to observe life activities in native cellular environments at nanoscale. Over the last 5 years, Dr Ju has developed the state-of-the-art pico-force (10-12 Newton) BFP technique as the first of its kind in Australia. Using this powerful nanotool, he has made conceptual advances on the inner workings of many mechanosensory proteins including the platelet integrin receptor in thrombosis (Nature Materials 2019; Nature Communications 2018; eLife 2018), the Apolipoprotein A-IV (Nature Communications 2018), glycoprotein Ib (eLife 2016) and von Willebrand factor (Science Advances 2018) in haematology and the syndecan receptor in cancer biology (Nature Communications 2014). This theme will combine BFP with high-resolution microscopy leading to a more advanced BFP imaging platform. It will become the first in the world capable of correlating the mechanical stimulation profile with the real-time cellular responses of a single platelet with the superior temporal, spatial, and force resolutions at 0.7 milli-second, 3 nano-meter, and 1 pico-newton respectively. The whole system provides precise controls and quantitative readouts in both mechanical and chemical terms, which is particularly suited for live-cell mechanosensing studies over the traditional methods in biochemistry and cell biology that are usually population-averaged and non-real-time. In future, it will further upgrade the platform in the combination of patch clamp to realise the single-molecule electrophysiology, imaging and manipulation in one system.

Additional Information

• Current PHD and/or Masters topics 1) Nature Materials (2019) –Chen Y#, Ju LA#, Zhou F, Liao J, Xue L, Yuan Y, Su QP, Jin D, Lu H, Jackson SP, and Zhu C (2019). An integrin αIIbβ3 intermediate affinity state mediates biomechanical platelet aggregation. Nature Mat 18(7): 760-769 doi: 10.1038/s41563-019-0323-6 Commented by Nature Materials (18(7):661–662) in the same issue. [IF 39.74] https://sydney.edu.au/news-opinion/news/2019/04/02/research-unlocks-biomechanic-mystery-behind-deadly-blood-clots.html  2) Nature Communications (2018) – Ju L, McFadyen JD, Al-Daher S, et al. (2018) Compression force sensing regulates integrin αIIbβ3 adhesive function on diabetic platelets. Nature Commun 9(1): 1084. doi: 10.1038/s41467-018-03430-6 [IF 12.53] https://www.hri.org.au/news/blood-clot-breakthrough-a-saviour-for-diabetics
 • Eligibility criteria / candidate profile You will have: 1) Academic knowledge in the discipline of biophysics, biomechanics, electrophysiology, cell biology and biochemistry; 2) Experience of instrumenting or operating single-molecule force spectroscopies such as atomic force microscopy, optical tweezers, magnetic tweezers, patch clamp electrophysiology systems, micromanipulation and microinjection systems, or other biomedical experimental devices such as rheometers and parallel plate flow chambers;3) Familiar with using two or more of Labview, ImageJ, AutoCAD, MATLAB, 3D-max, PRO-E, SolidWorks and other software. 
Preferred experience include: 1) Solid basic knowledge of biology and hands-on experience in PC2 biological laboratory, using flow cytometer, ELISA, Western blots, protein-protein interaction assays, protein/antibody purification and functional characterizations;  2) Capability of independently output processing models and drawings, be capable of CNC programming, use other conventional processing platform equipment to manufacture mechanical parts, and use 3D printers for part manufacturing; 3) Pre-doctoral track records with publications, conference papers, reports, professional or technical contributions with evidences of independent research ability; 4) Excellent oral and written communication skills.
 • Scholarship(s) / funding available 1) ARC Discovery Early Career Researcher Award (DECRA) DE190100609 “Mechanobiology: a new model of integrin activation by membrane tension”;  2) ARC Discovery Project DP200101970 (CI-A) “Integrin Activation by Fluid Flow Disturbance: Mechanobiology Approaches”

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Keywords

mechanobiology, Single molecule, Biophysics, patch clamp, Force spectroscopy, ion channel, membrane, biosensors, cardiovascular, Stroke, Platelet, Thrombosis, Piezo, fluorescence microscopy, Biomechanics, Red blood cell, diabetes

Opportunity ID

The opportunity ID for this research opportunity is: 2785

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