Department of Biochemistry and Molecular Biology

Biography

Dr. Yunfeng Chen received his PhD degree in BioEngineering at Georgia Institute of Technology, where he graduated with BioEngineering Outstanding Thesis Award. By combining the cutting-edge force spectroscopy, Biomembrane force probe, with cell fluorescence imaging, he studied platelet mechano-signaling and the binding, conformational dynamics and activation of integrins on the single-molecule and single-cell level. His researches advanced the field’s understanding on neutrophil adhesion/recruitment and its dysfunction by lupus, platelet mechanosensing via surface receptors GPIb and integrin αIIbβ3, and cell’s matrix rigidity-sensing. In 2016, Dr. Chen joined The Scripps Research Institute with the financial support of MERU Foundation. By combining in vitro bioengineering approaches (e.g., single-molecule/cell force spectroscopy and microfluidic-based techniques) with in vivo tests, he studied how atherothrombosis is associated with mechanobiological defects in platelets and blood plasma proteins.

Dr. Chen’s research is recognized nationally and internationally. He received Mary Rodes Gibson Memorial Award in Hemostasis and Thrombosis from the 59th American Society of Hematology Annual Meeting in 2017, American Heart Association (AHA) Postdoctoral Fellowship in 2019, Yuan-Cheng Fung Best Paper Award and ICBME Young Scholars Award from International Conference on Biomechanics and Medical Engineering in 2019. He is currently supported by an NIH R00 grant.

Research

"Mechano-medicine" is an emerging concept that tries to prevent and cure diseases by combining mechanobiology with biomedicine. The Chen lab focuses its research on the interface of mechanobiology, vascular biology and biomedicine. We use multidisciplinary approaches to 1) understand the mechanobiology of cells and molecules, including force-regulated molecular binding and conformational change, cell adhesion and mechano-signaling, in the vascular system; 2) shed light on the mechanobiology-related pathogenesis of vascular dysfunctions like thrombosis, atherosclerosis and cancer metastasis; and 3) eventually, develop mechanobiology-inspired therapeutics and research/diagnostic tools abiding the concept of ‘mechano-medicine’. The approaches of Chen lab can be summarized in seven M’s: Mechanics (investigating the mechanobiology of cell physiology and pathology); Microscopy (combining super-resolution imaging with force spectroscopy); Microfabrication (manufacturing microfluidic devices to realize high-throughput experimentation and develop mechanobiology-based diagnostic tools); Molecular engineering (designing and making protein mutants to understand disease pathology and explore potential therapeutic strategies); Molecular dynamics simulation (via collaboration, understanding the mechanisms underlying mechanobiological molecular behaviors); Mouse models (use transgenic mice to create disease models); and finally Mechano-medicine (designing and testing new therapeutics).

1. Receptor-mediated cell mechanosensing
We are investigating the mechanisms of different mechanosensing molecular machinery on the surface of varied vascular cells, primarily platelets but also including neutrophils, endothelial cells and metastatic cancer cells. We aim to distinguish different proteins or protein domains in the mechanosensing system as modules to accomplish certain mechanosensing tasks and steps: mechano-presentation, mechano-reception, mechano-transmission and mechano-transduction.

2. Vascular mechanomedicine

1. Arterial thrombosis, which describes the formation of abnormal blood clots in the artery, is a highly fatal disease that claims ~500,000 American lives per year. We are investigating how shear force-induced platelet activation contributes to arterial thrombosis, and how to inhibit it to safely prevent arterial thrombosis from becoming lethal. Two platelet mechano-receptors, GPIbα and integrin αIIbβ3 have been identified to play critical roles in platelet mechanosensing, and we are establishing novel strategies to suppress their activity.
2. Von Willebrand disease (VWD) is the most common inherited bleeding disorder. The pathogenesis of Type 2B and 2M VWDs are associated with mutations in the VWF A1 domain (VWFA1) – the binding site for platelet receptor GPIbα. We are investigating how these mutations cause mechanobiological deficiencies in VWF in mediating hemostasis. Related to translational medicine, we are bioengineering VWF to reinforce its hemostatic function, which will inspire a potent therapeutic approach for treating Type 2B and 2M VWDs.

3. Virus-related vascular dysfunctions
COVID-19 has been found to cause multiple dysfunctions in the vascular system, leading to thrombosis, thromboembolism and thrombocytopenia. However, the underlying mechanisms are not fully understood. We are investigating how infection of SARS-COV2 affects the adhesion and mechano-activation of platelets and VWF production in endothelial cells. The mechanobiology of SARS-COV2 virus-host cell interaction is also studied to better understand the viral infection process. Furthermore, we are exploring other viruses that cause vascular dysfunctions.

4. Integrin conformational changes and mechano-signaling
Integrins are mechano-receptors on cell surfaces that allow the cells to perform rigidity sensing and mechanosensing. We take the initiative to combine experimental and theoretical approaches to establish a biophysical model that comprehensively describes how mechanical force regulates the binding and conformational changes of integrins, which can be used to predict how mutations, drugs and diseases will affect integrin mechanosensing.

5. High-throughput microfluidic platform development
We are developing novel microfluidics-based high-throughput platforms to evaluate cell adhesion and shear-induced thrombogenesis. The developed devices will be used for basic science studies, disease diagnosis and drug screening.

Representative Recent Publications

1. Chen Y.*, Ju L. A.*, Zhou F., Liao J., Xue L., Su Q. P., Jin D., Yuan Y., Lu H., Jackson S. P., Zhu C., An integrin αIIbβ3 intermediate affinity state mediates biomechanical platelet aggregation. Nature Materials 18(7):760-769 (2019) (*Co-first authored). --Commented by Nature Materials (18(7):661–662) in the same issue

2. Chen Y.*†, Liao J.*, Yuan Z., Li K., Liu B., Ju L. A., Zhu C.†, Fast force loading disrupts molecular binding stability in human and mouse cell adhesions. Molecular & Cellular Biomechanics 16(3):211-223 (2019) (*Co-first authored) (†Co-correspondence). --Awarded Yuan-Cheng Fung Best Paper Award

3. Chen Y., Ruggeri Z. M., Du X., 14-3-3 proteins in platelet biology and glycoprotein Ib-IX signaling. Blood 131:2436-2448 (2018).

4. Zhou F., Chen Y., Felner E. I., Zhu C. and Lu H., Microfluidic auto-alignment of multiple protein patterns for dissecting multi-receptor crosstalk. Lab on a Chip, 18:2966-2974 (2018).

5. Chen Y., Lee H., Tong H., Schwartz M., Zhu C., Force regulated conformational change of integrin αVβ3. Matrix Biology 60-61:70-85 (2017).

6. Ju L.*, Chen Y.*, Li K.*, Yuan Z., Liu B., Jackson S. P., Zhu C., Dual Biomembrane Force Probe enables single-cell mechanical analysis of signal crosstalk between multiple molecular species. Scientific Reports, 7:14185 (2017). (*Co-first authored)

7. Ju L.*, Chen Y.*, Xue L., Du X., Zhu C., Cooperative unfolding of distinctive mechanoreceptor domains transduces force into signals. eLife 5:e15447 (2016) (*Co-first authored). --Featured in NSF Top Story

8. Elosegui-Artola A., Oria R., Chen Y., Kosmalska A., Pérez-González C., Castro N., Zhu C., Trepat X., Roca-Cusachs P., Mechanical regulation of a molecular clutch defines force transmission and transduction in response to matrix rigidity. Nature Cell Biology 18(5):540-8 (2016).

9. Rosetti F.*, Chen Y.*, Sen M., Thayer E., Azcutia V., Herter J. M., Luscinskas F. W., Cullere X., Zhu C., Mayadas T.N., A lupus-associated Mac-1 variant has defects in integrin allostery and interaction with ligands under force. Cell Reports 10, 1655-1664 (2015) (*Co-first authored).

10. Chen Y.*, Liu B.*, Ju L.*, Hong, J.*, Ji Q., Chen W., Zhu C., Fluorescence Biomembrane Force Probe: Concurrent Quantitation of Receptor-Ligand Kinetics and Binding-induced Intracellular Signaling on a Single Cell. Journal of Visualized Experiments 102, e52975 (2015).