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Ocular surface functions of SLURP1

SLURP1的眼表功能

基本信息

批准号：
10210610
负责人：
Shivalingappa Kottur Swamynathan
金额：
$ 41万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10210610
关键词：
Address Anti-Inflammatory Agents Behavior Cauterize Chemotaxis Cornea Corneal Neovascularization Development Diagnostic Disease Dry Eye Syndromes Endothelial Cells Endothelium Epithelial Cell Junction Extravasation Feedback Fibrosis Foundations Healthcare Systems Homeostasis Human Immune In Vitro Infiltration Inflammation Inflammatory Injury Intercellular Junctions Knock-out Knockout Mice Knowledge Laboratories Liquid substance Mediating Mission Mus Nature Neutrophil Infiltration Ophthalmologist Organism Outcome Outpatients PI3K/AKT Pathway interactions Patients Plasma Production Protein Family Proteins Publications Reporting Role Severities Signal Transduction Silver Nitrate Solid TNF gene Testing Transforming Growth Factor beta Tube Umbilical vein United States National Institutes of Health Urokinase Vascular Endothelial Cell Visit corneal epithelium cytokine experimental study immunoregulation member monolayer mouse model neovascularization neutrophil new therapeutic target novel therapeutics ocular surface public health relevance therapeutic target transcriptome transcriptome sequencing

项目摘要

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 surface that account for a significant burden on our healthcare system.

总结