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Jennifer Brackett, Laura Belen, Kortni Violette, Andy Whitlock; The Use of Soluble Muc-16 (CA-125) as a Clinically Relevant Biomarker and Endpoint in a Mouse Model of Dry Eye. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4310. doi: https://doi.org/.
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Inflammation is a significant part of Dry Eye Disease (DED), but no clear consensus between clinical and pre-clinical inflammatory endpoints has yet been established. Muc-16 is one of the primary membrane-associated mucins that form the protective glycocalyx on the ocular surface. Previous studies have shown that the extracellular domain of this glycoprotein is cleaved and released in the tear film of dry eye patients. This cleavage of Muc-16 has also been demonstrated in other systemic inflammatory conditions, such as ovarian cancer, for which soluble Muc-16 (CA-125) is a biomarker. The purpose of this study was to confirm the increase of soluble Muc-16 in the tear film of mice following Ora’s scopolamine/Controlled-Adverse-Environment (CAE) challenge.
Female C57/BL6 mice were subjected to Ora’s optimized dry eye model for 13 days or left untreated in normal housing conditions (naïve controls). Corneal staining was assessed on days 0, 4, 8, and 12 using a modified Micron III imaging system to assess the corneal damage due to the CAE challenge. The extent of staining was assessed using Ora’s proprietary grading scale along with an image analysis algorithm. Tear washes were collected and analyzed from both treatment groups 24 hours following the final exam. Tear levels of soluble Muc-16 were determined by ELISA for each sample. Muc-16 levels were normalized to the total protein concentration determined for each sample via BCA assay.
Corneal staining was significantly increased (p < 0.0001) in dry eye challenged mice compared to naïve controls by day 4 of the challenge and remained elevated throughout the entire study. Tear wash analysis at the conclusion of the challenge revealed a significant increase (p < 0.0001) of soluble Muc-16 in challenged mice compared to naïve controls. There was also a significant correlation (p= 0.0051, r2= 0.361) between the final corneal staining score and Muc-16 levels.
The study confirms that soluble Muc-16 (CA-125) release into the tear film following periods of prolonged dry eye stress is conserved between the mouse model and the human clinical condition. This further validates the scopolamine/CAE mouse model as a clinically relevant model for studying novel treatments for dry eye disease.
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