Mechanosensing mechanisms at the intestinal surface

Summary/Abstract A monolayer of epithelial cells lines pathways that are exposed to the external environment, such as the respiratory tract and digestive system, sequestering them from damaging external factors and acting as sensors of environmental changes. Microvilli, arrays of membrane bound actin protrusions that decorate the apical surface of almost all epithelial cells, form critical points of first contact between the epithelial cell and luminal contents. Here, microvilli play important roles in sensing and responding to chemical and mechanical stimuli. Yet the signaling-associated machineries within microvilli that drive these critical physiological functions, especially those that sense or respond to mechanical forces, are not well understood, representing a key knowledge gap. A major limitation has been that research on microvilli is predominantly conducted in cell culture model systems, which lack the 3D spatial ecosystem and mechanochemical signaling of cells within tissues, in vivo. We are uniquely positioned to overcome this hurdle by combining super-resolution functional imaging of microvilli in live animals and in vivo interactomics. We have identified novel ion channels that localize to epithelial cell microvilli across organs and are promising candidates that mediate mechanochemical signaling. We have also developed an in vivo systems approach to identify new microvillar associated signaling molecules. In this research program we will ask: 1) what are conserved molecular machineries that drive mechanochemical sensing in epithelial microvilli? 2) what are physiological consequences of microvillar signaling function across scales, from cell to organism? and 3) how does in vivo environment impact microvillar signaling inputs/outputs? This research will thus provide much-needed conceptual advances in our understanding of microvilli-mediated signaling in epithelial physiology and shed new light into the role of epithelial dysfunction in allergic and autoimmune disease.