Just as cells sense and respond to biological cues, cells also encounter diverse physical cues. These physical cues include compression, fluid flow, and stretch, among others. During development and in healthy tissues, a unique combination of biological and physical cues directs cellular growth, death, and migration. Conversely, perturbation of physical cues by trauma or disease drives progression of cancer, arthritis, and many other disease processes. Basic questions remain about the mechanisms by which cells discriminate among diverse physical cues and integrate this information to generate coordinated cellular responses. The research in this award is based on the hypothesis that cells position molecular sensors at strategic mechanosensitive sites, each of which initiates a unique response to a distinct physical cue. This research will use sophisticated molecular, bioengineering, and computational approaches to test this hypothesis and to identify the responsible molecular components. Elucidating fundamental mechanisms by which physical cues direct cellular behavior will advance our understanding of development and diseases, ultimately impacting our approach to disease prevention and treatment. By working at the interface of engineering, biophysics, and molecular biology, this project will answer fundamental questions in mechanobiology and provide a rich training environment for the student supported by this project and the greater lab community. The PI is committed to graduate education and also has a track record of community outreach through interactions with summer high school and college students and teachers at local schools.
Cellular structures such as focal adhesions or primary cilia play pivotal roles in sensing and responding to physical cues, including extracellular matrix stiffness and fluid flow. One of the biggest open questions in mechanobiology is "What are the mechanisms by which cells distinguish among physical cues to initiate unique responses?" Therefore, these studies evaluate the idea that spatially discrete receptor populations, at focal adhesions and primary cilia, support the ability of cells to distinguish among and generate unique responses to distinct physical cues. In addition, they will show whether receptor heteromerization is a common mechanism by which physical cues influence the activation of downstream effectors. This project applies novel molecular reagents, super-resolution imaging, and mass spectrometry, to investigate the sensitivity of distinct transforming growth factor-beta (TGF-beta) receptor populations to cytoskeletal tension and fluid flow. By taking advantage of a well-established model system, these studies lay critical groundwork for understanding the role of discrete receptor subpopulations and their mechanosensitive spatial organization in the cellular integration of signaling by biochemical and physical cues. Understanding these mechanisms will clarify how physical cues support cellular homeostasis, as well as the mechanisms by which trauma, microgravity, or fibrosis exacerbate disease.
