Student Presentation -- Saranne Mitchell
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Ph.D. Research Proposal, Thursday December 6, 2018 -- Biomechanical Predictors of Epithelial Extrusion

WEB 3780, Evans Conference Room, 1:30 pm

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Speaker: Saranne Mitchell. Advisor: Dr. Jody Rosenblatt


Abstract:

Epithelial cells function as a barrier that is critical for maintaining organ function, and also turnover by high rates of cell death and division in the body. Our lab has found that epithelial cells fated to die are forced out through a mechanism known as cellular extrusion. The regulation of this high turnover rate depends on the number of extrusions and cell divisions matching precisely and mismatch of these rates can lead to diseases marked by too many or too few cells. Previous work shows physical crowding at the tissue level controls extrusion, my proposed work will be the first to directly elucidate how compressive signals, propagate extrusion and how they are essential for controlling epithelial cell death. In order to achieve this goal, I propose to investigate cell extrusion by: cell density changes, individual cell and neighboring cell stiffness differentials, and associated tissue curvature. In aim 1, cellular density cells fated for extrusion will analyzed using Quantitative Phase Microscopy (QPM) an emerging technique that monitors changes in cell dry mass and mechanical properties. Because, the earliest indication that a cell will extrude is a Ca2+ flux, I will determine if density changes accompany this calcium event. Next, oncogenic cells, such as those expressing KRasV12 are measurably softer than wild type cells and extrude aberrantly basally and more frequently. In aim 2, I will investigate the effects of individual and neighboring cell stiffness on the rate and direction of extrusion. Lastly, epithelial cells typically extrude in curved highly contractile regions of tissues, suggesting that extruding cells may have reduced cell adhesions to the extracellular matrix (ECM) and that epithelial sheet buckling could create hotspots for extrusion. In aim 3, I will examine if experimentally curving epithelial sheets can trigger extrusion in buckled areas and if limited ECM contacts may promote extrusion. Understanding how buckling affects extrusion should have an impact on our understanding of how various cramping/inflammatory diseases could be restrained or enhanced depending on the type of tissue affected. Addressing these aims will allow us to uncover the biophysical properties of cells that contribute to extrusion and highlight how defects in these properties could contribute to tumor formation and metastasis.