New Insights into the Ocular Surface in Health and Disease

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 DESCRIPTION (provided by applicant): Conjunctival goblet cells are the major cell type that synthesize and secrete mucins for the maintenance of ocular surface integrity. Lack of mucins in the tear film due to goblet cells abnormality causes dry eye syndrome (DES) and affects millions of people's vision and life. The lack of knowledge regarding the regulatory mechanisms by which conjunctival epithelial cells differentiate to form goblet cells hampers the development of treatment regimens for DES. We found that inhibition of Notch via conditional expression of a dominant negative transcriptional coactivator mastermind-like 1 (dnMAML1) in the ocular surface epithelia (OSdnMAML1) suppressed goblet cell differentiation in mouse model. Compared to the wild-type mouse (OSWt), the ocular surface of the OSdnMAML1 exhibited conjunctival epithelial hyperplasia, aberrant desquamation, and impaired goblet cell formation. Moreover, OSdnMAML1 inhibited Krüppel-like transcriptional factor 4 and 5 genes (Klf4 and Klf5) expression and Muc5/ac synthesis. In contrast, conjunctival epithelium was expanded and differentiated into goblet cells in entire eyelid stroma of the TGFßRII conditional knockout (cKO) mice. The expanded TGFßRIIcKO conjunctival epithelium strongly expressed SAM-pointed domain containing ETS transcription factor (SPDEF), which plays a critical role in goblet cell differentiation in multiple organs. We hypothesize that intrinsic canonical Notch and TGFß signaling pathways and their interaction(s) play pivotal roles in conjunctival goblet cell differentiation. We propose three aims to test this hypothesis. Aim 1: To elucidate that Jagged1/Notch1 N1-ICD/Rbp-jκMAML1 Klf4/5 Muc5/ac axis is critical for the conjunctival goblet cell differentiation. Aim 2: To elucidate that TGFßRII Smads SPDEF Muc5/ac axis has a role in goblet cell differentiation. Aim 3: To delineate how Notch and TGFß pathways interact to come up with a physiological output for balanced goblet cell differentiation.