Ecto-5’-nucleotidase (CD73) mediates hepatocyte sensitivity to alcohol and alcoholic liver injury in mice

Effective cell migration, which plays an essential role in many physiological events, including tissue morphogenesis, wound healing and inflammatory responses, is dependent on dynamic remodeling of the actin-cytoskeleton. Type I coronins, a conserved class of WD40-repeat proteins, have been shown to facilitate this process by modulating the turnover of branch-actin networks at the leading edge. Recent work suggests that the Type I coronins, Coro1B and Coro1C, mediate the formation of membrane protrusions during cell migration and the stabilization of branchedactin networks within these protrusions. Despite these novel findings, however, our understanding of the function of Coro1B and Coro1C in directed migration remains incomplete. We therefore hypothesize that Coro1B and Coro1C regulate branched-actin dynamics during chemotaxis and haptotaxis. Using mouse tail fibroblasts that conditionally expressed Coro1B and Coro1C, we established matched-pair cell lines with and without coronins. To assess the effect of Coro1B and Coro1C on the locomotory behavior of cells during chemotaxis and haptotaxis, we utilized microfluidic chambers that generate chemically diffused and substrate-bound gradients, respectively. In addition, we used live-cell imaging and kymography to examine lamellipodia morphodynamics in the matched-pairs. In the absence of Coro1B and Coro1C, cells lack directionality and migrate more slowly than their WT counterparts. Coro1B and Coro1C null cells also have lower protrusion durations and increased protrusion rate as compared to WTs. We conclude that Coro1B and Coro1C are highly involved in regulating actin dynamics at the leading edge which is required for effective lamellipodial formation and directed migration. The role of endothelial MERTK in leukocyte transendothelial migration and the inflammatory response Authors: Yitong Li, Claire Doerschuk, Keith Burridge Department of Cell Biology and Physiology, UNC Chapel Hill Abstract: Leukocyte transendothelial migration (TEM) is an important process during inflammation and immune response. During leukocyte transmigration, endothelial cells (ECs) form apical membrane protrusions called transmigratory cups surrounding the Leukocyte transendothelial migration (TEM) is an important process during inflammation and immune response. During leukocyte transmigration, endothelial cells (ECs) form apical membrane protrusions called transmigratory cups surrounding the adherent leukocyte to facilitate TEM. The morphological similarity between the transmigratory cup and phagocytic cup led us to MERTK, a receptor tyrosine kinase known to regulate actin reorganization in macrophages during phagocytosis. Despite extensive documentation of MERTK’s involvement in immune response and tumor progression, few studies have illuminated its function in the vasculature system. My study evaluates the role of endothelial MERTK in leukocyte TEM and the inflammatory response both in vitro and in vivo. My preliminary analysis with in vitro TEM demonstrated that more transmigration events were observed when MERTK is removed from ECs. Further examination revealed that ECs devoid of MERTK failed to restore tight injunctions after leukocyte TEM. Consistent with these in vitro findings, in vivo experiments assessing the lung endothelium permeability in healthy mice demonstrated that vasculature in Mertk-/mice were more leaky than that of wild type mice. Based on these data, I hypothesized that endothelial MERTK affects leukocyte TEM by regulating junction integrity and actin cytoskeleton. To further test my hypothesis, I will evaluate EC permeability changes during TEM in vitro using siRNA knockdown or MERTK inhibitors. I will also analyze lung endothelium permeability and leukocyte transmigration during pneumonia in EC-specific Mertk-/mice. Results from my study will characterize novel functions of MERTK in ECs and identify potential pharmaceutical targets for inflammatory diseases. Role of B Cell Receptor signaling in Pancreatic Ductal Adenocarcinoma