New Insights into the Ocular Surface in Health and Disease

对眼表健康和疾病的新见解

• 批准号: 9135400
• 负责人: CHIA-YANG LIU
• 金额: $ 42.58万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135400
• 关键词: Ablation; Adult; Affect; Alleles; Attenuated; Biochemical; Breeding; Cell Differentiation process; Cells; Conjunctival Epithelium; Data; Data Set; Development; Disease; Dominant-Negative Mutation; Dry Eye Syndromes; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Exhibits; Eyelid structure; Film; Genes; Genetic; Goals; Goblet Cells; Health; Human; Hyperplasia; Keratoconjunctivitis Sicca; Knock-out; Knockout Mice; Knowledge; Lead; Life; LoxP-flanked allele; Luciferases; Maintenance; Mediating; Metaplasia; Molecular; Morphogenesis; Mouse Strains; Mucins; Mus; Organ; Output; Pathogenesis; Pathway interactions; Physiological; Platelet Factor 4; Play; Publishing; Regulation; Repression; Research; Role; Signal Pathway; Signal Transduction; Staging; Testing; Therapeutic; Time; Transcription Coactivator; Transforming Growth Factor beta; Transgenic Mice; Treatment Protocols; Vision; Wild Type Mouse; base; cell type; eye dryness; in vivo; insight; interest; mouse model; notch protein; novel; ocular surface; postnatal; promoter; receptor; transcription factor

 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.