Integrin-mediated adhesions, such as podosomes and invadopodia, are the biophysical anchor to sense and to translate mechanobiological signals into various cellular events. Mechanobiology is an emerging research frontier that aims to understand how cells and tissues sense and respond to mechanical stimuli. Exposure to normal mechanical stimuli is essential to maintain physiological functions, such as cell migration, cell fate determination, and tissue organization. Abnormal mechanical stimuli, however, can lead to tissue malfunction and diseases.
Previously, we have developed an experimental platform of RGD supported lipid membranes to uncover important mechano-biological signalling pathways in integrin-mediated adhesions and actin cytoskeletal regulations. With solid in-house training in molecular and cell biology and cutting-edge microscopy techniques, this PhD project will focus on one of the following questions of mechanobiology-related issues.
- The role of matrix rigidity in orchestrating podosome assembly and atherosclerosis. Vascular smooth muscle cells (VSMC) are the fundamental building block of the artery. Stiffness changes of arteries due to vascular injuries or excess deposition of cholesterol plaques would lead VSMC to assemble podosome and migrate. The podosome assembly and irregular migration of VSMC often marks the early stage of atherosclerosis. This research project will focus on revealing the mechanism, i.e. the regulation of actin polymerization and stabilization over stiffness-defined substrates.
- PI3K-mediated Rho GTPase activation in the cancer invadosome. Rho GTPases play active roles in cytoskeleton regulation and cancer invadosome formation. Our previous work has shown that the biogenesis of PI(3,4,5)P3 lipids at the invadosome core serves as the upstream signal to regulate Rho GTPases activities. In this project, we will further employ screening approaches to identify key PI(3,4,5)P3-mediated factors and to demonstrate novel inhibitory pathways to suppress the invasive migration of cancer cells.
- Phosphatidylinositol-mediated adhesion signalling and matrix resorption at the osteoclast podosome. Bones are composed of living matters and constantly undergo remodelling. Osteoclasts derived from monocyte lineages in the red bone marrow play an important role in bone resorption by breaking down bone matrix. Osteoclasts utilize membrane receptor integrin alphaVbeta3 to form podosome and assemble matured sealing zone. Hyperactivated osteoclasts often lead to loss of bone mass and osteoporosis. In this research project, we will pursue a detailed mechanistic understanding in phosphatidylinositol-mediated endocytosis, bone resorption, and metastasis-induced osteolysis.
Dr Yu received the PhD degree from the University of California, Berkeley in 2007. With the distinguished fellowship from NSC Taiwan, he completed the postdoctoral training in Mechanobiology Institute, National University of Singapore. He joined the University of Hong Kong in 2014. He has made major scientific contributions in mechano-sensitive signal transductions of cell-matrix adhesions. He utilized integrative approaches of micro/nano-patterning of functionalized supported membranes and quantitative live-cell fluorescence microscopy to decipher the regulation of mechano-chemical events of the cell.
Specifically, he identified three novel pathways: (i) adhesion transformations to protrusive invadosome (PNAS 2011; Cell Reports 2013); (ii) force-dependent intgrin-beta3 endocytosis (Nature Communications 2015); and (iii) myosin-1e and phosphatidyl-inositol signaling at the podosome (MBoC 2019). He has received the research output prize by SRT of D&R in HKU (2016). He was the keynote speaker and discussion leader in Gordon Research Seminar: Adhesion Receptor Signaling (2012 and 2014, respectively). He was also an invited speaker in Max Planck-Croucher Symposium (2018).
More information: http://hub.hku.hk/cris/rp/rp01930
Faculty information, funding opportunities and application deadlines: https://www.findaphd.com/phds/program/biomedical-research-hku-li-ka-shing-faculty-of-medicine/?i586p4119