Integrative Approaches for Probing Cell Mechanotransduction in Health and Disease

Boston University (Charles River Campus), Boston MA

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Abstract

PROJECT SUMMARY Notch receptors are mechanically activated transmembrane proteins that regulate cell fate, differentiation, proliferation, adhesion, and many other critical processes. Most studies to date have focused on understanding Notch from biochemical and genetic perspectives and have only recently been explored as a mechanoreceptor. Given Notch's varied roles in both standard and pathological states, it is necessary to formulate an integrated mechano-chemical perspective of Notch signaling and regulation, as such an outlook for a comprehensive understanding of this critical and evolutionarily conserved signaling pathway. In this project, my lab will leverage our expertise in chemical probe development and molecular tool design to address sharply focused mechanistic questions regarding Notch mechanotransduction. To distinguish our contributions from those of others, we will pursue a multi-scale understanding of the pathway by combining single molecule studies and high-resolution imaging to understand how the activation of the receptor is coupled to biomechanical events that occur within the cell. In particular, new correlative light and electron microscopy will be developed and applied to determine the precise timing and location of events surrounding Notch signal transduction. In addition, to address important questions regarding the source and magnitude of the external forces experienced by cells, we will also create synthetic versions of Notch and apply them as genetically encoded “tensiometers.” Successful execution of this work will provide deep insights into the synergy between biochemical and mechanical cues and increase our overall understanding of how cells sense and interpret mechanical information.