Although 15-20% of Americans suffer from allergic conjunctivitis, current treatments are limited to anti-histamines and mast cell stabilizers that ar often ineffective. The long-term goal of the proposal is to develop a new treatment for allergic conjunctivitis that could also be used for allergies of the lung, skin, and nose along with other inflammatory diseases of the ocular surface, such as dry eye. The new treatment is an anti-inflammatory and pro-resolution lipid mediator, the D-series resolvins compared to E-series resolvins currently in a clinical trial. Conjunctival goblet cell over-secretion of mucous includin the mucin MUC5AC is one of the symptoms of allergic conjunctivitis that include itching, conjunctival redness, tearing, and chemosis. D-, but not E-, series resolvins have two modes of action. They block histamine and leukotriene over-stimulation of goblet cell secretion and themselves activate a small amount of secretion to protect the ocular surface while the over-secretion is being reset. E-series do not increase secretion. The current proposal will focus on determining how pro-resolution mediators act at a molecular level to counter-regulate proinflammatory mediator stimulation of goblet cell mucin secretion both in culture and in vivo in a mouse model of allergic conjunctivitis. Research will focus on the following aims: 1. Determine the cellular mechanisms the D- and E-series resolvins use to stimulate goblet cell mucin secretion and if goblet cells are the source of the resolvins and other lipid mediators;2. Unravel the molecular mechanisms D- and E-series resolvins use to activate protein kinases to interact with histamine and leukotriene receptors to counter-regulate their action;and 3. Ascertain the efficacy of D- compared to E-series resolvins to terminate goblet cell secretion and improve symptoms in a murine model of allergic conjunctivitis.
For aim 1 RvD1, aspirin triggered (AT)-RvD1, and RvE1 will be used to stimulate human conjunctival goblet cells in culture. The receptors and cellular signaling pathways activated by the resolvins including phospholipase C and D and PI-3K will be investigated using siRNA, pharmacological inhibitors, and adenovirus constructs. In addition, the production of pro-inflammatory and pro-resolution mediators will be determined by lipidomic measurements on goblet cells in culture.
For aim 2, CHO cells transfected with a pro-inflammatory histamine or leukotriene receptor and a pro-resolution receptor and cultured human goblet cells will be used. Protein kinases predicted to phosphorylate the pro-inflammatory mediator receptors will be studied to determine if RvD1, AT-RvD1, and RvE1 activate the protein kinases and counter-regulate the histamine or leukotriene receptor to block its activity and terminate mucin secretion. siRNA, pharmacological inhibitors, and adenovirus constructs will be used for this aim.
For aim 3, a mouse model of severe allergic conjunctivitis will be used with ovalbumin as the allergen. Resolvins compared to anti-histamines will be used to determine if they decrease MUC5AC secretion and goblet cell proliferation, ameliorate the clinical symptoms of allergic conjunctivitis, and terminate infiltraton of inflammatory cells.

Public Health Relevance

Although 15-20% of Americans suffer from allergic conjunctivitis, current treatments are limited to anti-histamines and mast cell stabilizers that ar often ineffective. We propose a new treatment for allergic conjunctivitis, the use of the anti-inflammatory, pro-resolution lipid mediators known as resolvins. D- and E-series resolvins have the potential to decrease the symptoms of allergic conjunctivitis by blocking goblet cell mucin secretion stimulated by histamine, leukotrienes, and other pro-inflammatory mediators.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-H (02))
Program Officer
Mckie, George Ann
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Schepens Eye Research Institute
United States
Zip Code
García-Posadas, Laura; Hodges, Robin R; Diebold, Yolanda et al. (2018) Context-Dependent Regulation of Conjunctival Goblet Cell Function by Allergic Mediators. Sci Rep 8:12162
Kaye, Rebecca; Botten, Nora; Lippestad, Marit et al. (2018) Resolvin D1, but not resolvin E1, transactivates the epidermal growth factor receptor to increase intracellular calcium and glycoconjugate secretion in rat and human conjunctival goblet cells. Exp Eye Res 180:53-62
Fostad, Ida G; Eidet, Jon R; Lagali, Neil S et al. (2017) Identification of Objective Morphometric Markers of Xerostomia in the Oral Mucosa Epithelium with In Vivo Confocal Microscopy. Microsc Microanal 23:88-96
English, Justin T; Norris, Paul C; Hodges, Robin R et al. (2017) Identification and Profiling of Specialized Pro-Resolving Mediators in Human Tears by Lipid Mediator Metabolomics. Prostaglandins Leukot Essent Fatty Acids 117:17-27
Lippestad, Marit; Hodges, Robin R; Utheim, Tor P et al. (2017) Resolvin D1 Increases Mucin Secretion in Cultured Rat Conjunctival Goblet Cells via Multiple Signaling Pathways. Invest Ophthalmol Vis Sci 58:4530-4544
Islam, Rakibul; Eidet, Jon Roger; Badian, Reza A et al. (2017) Tissue Harvesting Site and Culture Medium Affect Attachment, Growth, and Phenotype of Ex Vivo Expanded Oral Mucosal Epithelial Cells. Sci Rep 7:674
Hodges, R R; Li, D; Shatos, M A et al. (2017) Lipoxin A4 activates ALX/FPR2 receptor to regulate conjunctival goblet cell secretion. Mucosal Immunol 10:46-57
Belmonte, Carlos; Nichols, Jason J; Cox, Stephanie M et al. (2017) TFOS DEWS II pain and sensation report. Ocul Surf 15:404-437
García-Posadas, Laura; Contreras-Ruiz, Laura; Soriano-Romaní, Laura et al. (2016) Conjunctival Goblet Cell Function: Effect of Contact Lens Wear and Cytokines. Eye Contact Lens 42:83-90
Ryan, Denise S; Bower, Kraig S; Sia, Rose K et al. (2016) Goblet cell response after photorefractive keratectomy and laser in situ keratomileusis. J Cataract Refract Surg 42:1181-9

Showing the most recent 10 out of 40 publications