Summary The persistent gap in our understanding of ocular surface immunomodulation is a barrier for developing new therapies for inflammatory disorders that are responsible for a bulk of outpatient visits to an ophthalmologist. Previous publications from our laboratory established that the secreted Ly6/uPAR related protein-1 (SLURP1), a member of the Ly6 family of proteins is an immunomodulatory molecule at the ocular surface that: (i) is highly expressed in the corneal epithelium and secreted to the tear fluid; (ii) acts as a soluble scavenger of urokinase- type plasminogen activator (uPA); (iii) inhibits human umbilical vein endothelial cell (HUVEC) tube formation; (iv) suppresses neutrophil chemotaxis and transmigration through confluent endothelial monolayer in vitro; and (v) stabilizes epithelial cell junctions and suppresses TNF-α-induced cytokine production consistent with an anti-inflammatory function. Collectively, these studies identified SLURP1 as a potential therapeutic target for inflammatory disorders of the ocular surface. Here we propose to build upon these salient findings by testing the central hypothesis that ‘SLURP1 suppresses corneal angiogenic inflammation and neutrophil recruitment by regulating the TGF-β- and uPA-activities that promote NFκB-mediated production of pro-inflammatory molecules’. This hypothesis is supported by our prior publications described above, and exciting results from our unpublished preliminary studies wherein Slurp1 knockout (Slurp1X-/-) mouse corneas displayed dense corneal neovascularization and excessive neutrophil influx five days after silver nitrate cautery. Furthermore, RNA-Seq comparison of the naïve wild type and Slurp1X-/- mouse corneal transcriptomes identified key activators of angiogenic inflammation including TGF-β and NFκB pathway components to be upregulated in the absence of Slurp1, lending additional support for this hypothesis. We will test this hypothesis by employing mouse models and in vitro studies to pursue the following Specific Aims: Aim 1). Test the hypothesis that Slurp1 protects the cornea from undesirable angiogenic inflammation by suppressing unmitigated TGF-β and uPA activities that feed into NFκB pathway; Aim 2). Test the hypothesis that Slurp1 suppresses neutrophil influx into healthy corneas by promoting neutrophil maturation and clearance, and interfering with their extravasation; and Aim 3). Test the hypothesis that SLURP1 is negatively correlated with the severity of human dry eye disease and a useful therapeutic target for ocular surface inflammatory disorders. By elucidating promising new information related to the immunomodulatory functions of SLURP1, an abundantly expressed yet understudied protein, anticipated outcomes of this proposal directly address the NIH mission of ‘seeking fundamental knowledge about the nature and behavior of living systems’ and offer the potential for validating a novel therapeutic target for inflammatory disorders of the ocular sur...