Cortical excitability as a mechanism for epithelial barrier maintenance: A joint experiment-theory systems approach

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Multicellular organisms evolved multiple adaptations to separate and protect themselves from the surrounding environment, which is frequently hostile to the interior of the organism. Epithelial tissues in our bodies play the guardian role enveloping the entire body (skin) as well as wrapping each of our organs. This protective role relies on the formation and continuous maintenance of tight junctions between individual epithelial cells. These junctions have to be sufficiently tight to prohibit entry of pathogens, foreign proteins, chemicals and gases as well as to keep inside the bodily fluids. Multiple debilitating human diseases are associated with loss of these protection barriers in the gut, lungs, skin, mucosa, etc. However, epithelial tissues are live and individual cells within epithelium undergo cell divisions, death and rearrangements, all process that require that the junctions between cells must be plastic and dynamic. How the barrier function is maintained within living and actively developing epithelia remains still poorly understood. Studying frog embryonic epithelium, we recently discovered that cell-cell junctions in this dynamic tissue undergo random failures (ruptures) due to the increased mechanical tension but are rapidly repaired by a sentinel mechanism that is somehow triggered by the rupture. Our data suggest that the molecular mechanism of this repair process may involve a fundamental systemic property known as excitability, which is observed in complex nonlinear systems across all areas of science and technology. We recently described a likely similar excitable behavior in frog and starfish oocytes and this discovery, published in November 2015 by Nature Cell Biology, was featured in the BBSRC News and Business Magazine. In this proposal we will explore the hypothesis of the excitable nature of the epithelium repair mechanism in depth and breadth using both modern experimental methods and computational modelling. We will identify the molecular details of this mechanism and will seek points of intervention within this mechanism to be able to eventually translate our results into novel medical therapies.