Project 3: Sulfs and Wound Repair in Mucosal Epithelium Mucosal epithelia covering the respiratory tract and cornea are vulnerable sites for the entry of pathogens and noxious substances. Upon injury, these epithelia must be rapidly repaired to restore function and to limit infection. Our work will focus on two novel sulfatases, known as Sulf-1 and Sulf-2, which we have cloned and characterized in human and mouse. The Sulfs are extracellular endosulfatases, which act on heparan sulfate proteoglycans (HSPGs). HSPGs influence a huge variety of processes by binding to a multiplicity of signaling molecules such as chemokines, growth factors, and morphogens (e.g., Wnts). The Sulfs """"""""edit"""""""" the sulfation status of HSPGs by selectively removing the 6-O-S from glucosamine within HS chains. In so doing, the Sulfs modulate HSPG-ligand interactions and regulate signaling events and infection. The Sulfs promote Wnt signaling in development and cancer. Since Wnt signaling is also involved in epithelial wound responses, we have investigated the role of the Sulfs in the repair of mucosal epithelia. Our studies reveal that Sulf is expressed in lung type II alveolar epithelial cells (AT-II), which are critical in the the reepithelialization of injured alveolar walls. Moreover, Sulf regulates Wnt signaling and cell growth of an alveolar epithelial cell line. We will investigate the involvement of Sulfs in the repair of scratched monolayers of cultured alveolar cells, as a model of acute lung injury. Our second focus will be wound repair of corneal epithelium. Here, we found that Sulf is dramatically upregulated upon scratching of mouse cornea. In a cell culture model of human corneal epithelial cells, Sulf is required for repair of scratched monolayers. Our proposed studies of wound repair of alveolar epithelium and corneal epithelium will take advantage of established and novel methods for inhibiting the activity and expression of the Sulfs, including RNAi, antibodies, a small molecule inhibitor of the Sulfs, and Sulf null mice (single and double). We hypothesize that the Sulfs are pivotal in epithelial repair processes, by promoting Wnt-dependent cell growth and cell migration. By understanding the roles of Sulfs in the repair of distal airways and cornea, new methods for enhancing wound repair of these highly vulnerable mucosal epithelia may emerge. Projects 1, 2, and 4 will investigate related aspects of the Sulfs. We will extensively colloborate with them and Cores B and C.
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