This proposal investigates the mechanisms responsible for loss of mucus-producing conjunctival goblet cells in dry eye. Dry eye is one of the most prevalent medical conditions that decreases quality of life due to irritation symptoms and visual disturbance at a great cost to society. A hallmark of aqueous tear deficiency is loss of conjunctival goblet cells. Goblet cell secretions are essential for maintaining a stable tear film. Our preliminary data indicated that goblet cells are components of the ocular mucosal immune system and that goblet cell maturation and mucus secretion is regulated by T-helper cytokines. The T-helper 2 cytokine IL-13 promotes goblet cell maturation and mucus production while the Th1 cytokine interferon gamma inhibits goblet cell maturation. Interferon gamma increases in the conjunctiva in dry eye. This grant investigates the hypothesis that interferon gamma represses conjunctival goblet cell maturation by increasing expression of FoxA2, a transcriptional repressor of MUC5AC mucin, as well as the IL-13 decoy receptor, IL-13 receptor alpha 2 that avidly binds IL-13 and inhibits IL-13 signaling in goblet cells. Three specific gains are proposed to investigate this novel hypothesis. This proposal addresses a gap in knowledge regarding the mechanism of goblet cell loss in dry eye. At the conclusion of this project, we will better understand the molecular mechanisms by which interferon gamma antagonizes the goblet cell promoting activity of IL-13. We will also determine whether IL-13 supplementation and/or interferon gamma neutralization have therapeutic potential for promoting goblet cell maturation in dry eye. The end product of this project will be a fundamental new understanding of the regulation of conjunctival secretory function by these T-helper cytokines and novel strategies to maintain goblet cell promoting environment in the conjunctiva in dry eye disease.

Public Health Relevance

Loss of secretory goblet cells in the conjunctiva in dry eye is associated with greater irritation symptoms and ocular surface disease. We hypothesize that goblet cell maturation in dry eye is repressed by the T helper cytokine, interferon-gamma. The overall goal of this proposal is to define the mechanisms by which interferon-gamma inhibits goblet cell maturation in dry eye and discover new and novel ways to manipulate the balance of T-helper cytokines to promote goblet cell differentiation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY011915-15S1
Application #
8787847
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
1997-08-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
15
Fiscal Year
2014
Total Cost
$101,625
Indirect Cost
$34,884
Name
Baylor College of Medicine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Deng, Ruzhi; Su, Zhitao; Lu, Fan et al. (2014) A potential link between bacterial pathogens and allergic conjunctivitis by dendritic cells. Exp Eye Res 120:118-26
Zhang, X; Schaumburg, C S; Coursey, T G et al. (2014) CD8(+) cells regulate the T helper-17 response in an experimental murine model of Sjogren syndrome. Mucosal Immunol 7:417-27
Zhang, Xiaobo; De Paiva, Cintia S; Su, Zhitao et al. (2014) Topical interferon-gamma neutralization prevents conjunctival goblet cell loss in experimental murine dry eye. Exp Eye Res 118:117-24
McClellan, Andrew J; Volpe, Eugene A; Zhang, Xiaobo et al. (2014) Ocular surface disease and dacryoadenitis in aging C57BL/6 mice. Am J Pathol 184:631-43
Foulks, Gary N; Pflugfelder, Stephen C (2014) New testing options for diagnosing and grading dry eye disease. Am J Ophthalmol 157:1122-9
Villani, Edoardo; Baudouin, Christophe; Efron, Nathan et al. (2014) In vivo confocal microscopy of the ocular surface: from bench to bedside. Curr Eye Res 39:213-31
Tung, Cynthia I; Perin, Andrew F; Gumus, Koray et al. (2014) Tear meniscus dimensions in tear dysfunction and their correlation with clinical parameters. Am J Ophthalmol 157:301-310.e1
Deng, Ruzhi; Su, Zhitao; Hua, Xia et al. (2014) Osmoprotectants suppress the production and activity of matrix metalloproteinases induced by hyperosmolarity in primary human corneal epithelial cells. Mol Vis 20:1243-52
Coursey, Terry G; Bohat, Ritu; Barbosa, Flavia L et al. (2014) Desiccating stress-induced chemokine expression in the epithelium is dependent on upregulation of NKG2D/RAE-1 and release of IFN-? in experimental dry eye. J Immunol 193:5264-72
Alex, Anastasia; Edwards, Austin; Hays, J Daniel et al. (2013) Factors predicting the ocular surface response to desiccating environmental stress. Invest Ophthalmol Vis Sci 54:3325-32

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