Mechanosensitive mechanisms regulating cellular coordination during tissue morphogenesis and patterning - Abstract The long-term goal of this research program is to understand and identify mechanosensitive mechanisms that regulate cellular transcription and cell-to-cell signaling during normal tissue morphogenesis and patterning. For instance, our sense of touch, regulation of blood pressure, osmotic regulation, and sense of balance are all regulated by mechanosensitive proteins throughout the body. Our particular interest is in the role that mechanosensitive ion channels and structures, such as the primary cilia, play in the transfer of electrical currents, ions, and second messengers, to promote transcriptional changes and altered cell-to-cell communication. Deciphering these changes is critical for understanding how cellular communication within a complex tissue environment is coordinated and maintained. The importance of mechanosensitive signaling is underscored by the association of many disease states with compromised mechanotransduction, including congenital heart defects, muscle degeneration, arrhythmias, polycystic kidney disease, and numerous neuronal disorders. Despite this, a relatively small amount is known at the level of normal, healthy tissues about how mechanosensitive proteins go from sensing force to eliciting changes in cellular signaling and/or function. Our interest therefore lies in understanding how cells assimilate ‘data’ from mechanosensitive inputs to alter transcriptional programs and cell-to-cell communication to coordinate individual cellular movements within tissues. To carry out this work, we capitalize on our strengths in studying tissue patterning in the zebrafish along with sophisticated 3-dimensional in vitro tissue modeling assays where we can tune and control mechanical forces. From our work we aim to understand: 1) how mechanotransduction affects intracellular signaling, particularly though the activation of transcriptional networks and altered gene expression, and 2) how mechanosensation affects intercellular signaling activities to alter patterning of tissues. We target and utilize highly mechanosensitive cells, such as endothelial cells, smooth muscle cells, and epidermal cells, for our studies to understand both generalizable and cell type specific roles of mechanotransduction in regulating gene expression, cellular motility, and cell-to-cell communication. With this award, we will continue to carry out cutting-edge work aimed at unravelling the role of mechanosensitive proteins and their regulation of cellular differentiation, transcriptional programs, and tissue patterning events.
