The PI?s laboratory studies cell mechanobiology at the molecular tension level. Force is essential for the life of cells. Integrin-transmitted cellular force at the cell-matrix interface mechanically drives short-term cellular functions such as cell adhesion, contraction and migration. In long term, cellular force is also transduced to biochemical signals to regulate cell proliferation, differentiation, cancer cell metastasis, etc. Because of its fundamental importance, integrin-transmitted cellular force has been extensively studied at the bulk level by the well-developed cell traction force microscopies. However, integrin tension, the force transmitted by individual integrin molecules, despite its fundamental role in integrin signaling, is much less understood in most cellular functions. The PI?s lab specializes in studying cell mechanobiology using innovative molecular tension tools that measure, map and manipulate integrin tension in live cells. A tension sensor named ITS was developed by the PI to convert integrin tension to fluorescent signal and enable integrin tension mapping directly by fluorescence imaging with high spatial resolution. A tension modulator named TGT was developed to quantitatively restrict integrin tension in whole cells under a designed level for the study of regulative role of integrin tension in specific cellular functions. With these tools, the PI?s lab initiated the study of integrin tension in migrating cells, platelets and micro-sized invadopodia of cancer cells. The preliminary experiments have demonstrated the feasibility and versatility of these integrin tension tools in the research of cell mechanobiology at the molecular tension level. With these innovative tension tools, the elusive integrin tension can now be visualized, quantified and controlled along with cell structure and biochemical factors in live cells with comparable resolution, sensitivity and precision. In next five years, the PI?s lab will study the correlation, co-localization and causality among integrin tension, cell structure and local biochemical activities in live cells. The MIRA fund provides the PI?s lab with the flexibility to continue the study of integrin tension in three distinct cellular processes. The PI will combine molecular tension tools, genetic methods and fluorescence imaging to investigate the range, source, distribution and function of integrin tension in migrating cells, and reveal how cells exert and control integrin tension locally to coordinate cell protrusion and retraction. For platelet study, the force source and biological function of integrin tension during platelet adhesion, contraction and aggregation will be investigated in both 2D and 3D contexts. The integrin tension map will also be tested as a diagnostic assay for the assessment of platelet activity in stemming bleeding. For invadopodium study, the role of integrin tension in invadopodium formation and matrix degradation during cancer cell invasion will be comprehensively investigated. The proposed research will reveal valuable insights to the fundamental role of integrin tension in these various cellular processes. This project will also provide the field with innovative molecular tension sensor and tension modulator that are expected to be widely useful for cellular force study with unprecedented resolution and sensitivity.
Integrins and integrin-transmitted cellular force are critical for many cellular and physiological functions which are the foundation of human health. Aberrant cellular force generation and regulation lead to a variety of human diseases. This project will apply innovative molecular tension tools to study the fundamental role of cellular force in cell migration, platelet functions and cancer cell invasion. This study will advance our understanding of cell mechanobiology and the associated pathology to the molecular tension level.
|Zhao, Yuanchang; Wang, Yongliang; Sarkar, Anwesha et al. (2018) Keratocytes Generate High Integrin Tension at the Trailing Edge to Mediate Rear De-adhesion during Rapid Cell Migration. iScience 9:502-512|