Clusterin at the Ocular Surface

眼表面的聚集蛋白

• 批准号: 9755442
• 负责人: M. Elizabeth Fini
• 金额: $ 55.67万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755442
• 关键词: Address; Adverse effects; Affect; Aging; Anti-inflammatory; Apical; Basic Science; Binding; Biochemical; Biological Assay; Biological Response Modifier Therapy; Blindness; Cells; Characteristics; Clinical; Contact Lenses; Cornea; Cyclosporine; Cytoprotection; Data; Disease; Drops; Dry Eye Syndromes; Environment; Environmental Exposure; Epithelial; Epithelium; Experimental Models; Eye; Galactose Binding Lectin; Galectin 3; Genes; Genetic; Glycocalyx; Glycoproteins; Human; Hydration status; In Vitro; Inflammation; Inflammatory; Journals; Knockout Mice; Knowledge; Left; Light; Liquid substance; Lubrication; MMP9 gene; Measurement; Medical; Medicine; Methods; Modeling; Molecular; Mus; Nature; Operative Surgical Procedures; Ophthalmologic Surgical Procedures; Pain; Pathway interactions; Patients; Penetration; Peptides; Pharmaceutical Preparations; Positioning Attribute; Property; Proteins; Proteolysis; Pruritus; Publishing; Redness; Research; Research Personnel; Role; Squamous Metaplasia; Stress; Structure; Surface; Symptoms; Therapeutic; Tissues; United States Food and Drug Administration; United States National Institutes of Health; Work; corneal epithelium; corneal scar; eye dryness; in vivo; inflammatory milieu; innovation; intercalation; mouse model; novel; novel strategies; novel therapeutics; ocular surface; prevent; proteostasis; response; seal; sulfated glycoprotein 2; tear proteins

7. PROJECT SUMMARY/ ABSTRACT Dry eye syndrome is a common affliction of the eye that affects millions of people. Dry eye is brought on by aging, eye surgery or environmental exposure and is also an adverse effect of contact lens wear, and topical eye medications. Symptoms include pain, burning, itching, redness, sensitivity to light and other discomfort. If left untreated, severe cases may result in vision loss due to corneal scarring. New research from this research team, recently published in the NIH-supported journal PLOS ONE, suggests a new approach to treating dry eye. Using an experimental mouse model, the researchers found that the natural tear protein known as clusterin selectively binds to the ocular surface barrier disrupted by desiccating stress in an all-or-none manner, while also preventing further damage. Known properties of clusterin suggest it may further protect against the upstream effects of inflammatory cascade activation and subsequent squamous metaplasia. The proposed research will investigate this previously unrecognized, endogenous protective mechanism. The planned studies make use of the mouse experimental model and a quantitative functional assay for ocular surface barrier disruption, and take advantage of mouse genetics. The specific aims are: 1) to determine the molecular nature of clusterin intercalation into the ocular surface glycocalyx, and how it might relate to the all- or-none effect; 2) to document the role of clusterin in anti-proteolysis, the effects of proteolysis on the capacity for clusterin binding, and the relationship between the proteolytic and clusterin pathways; 3) to define the endogenous clusterin protection pathway and its role in maintaining an anti-inflammatory environment at the ocular surface. The impact of this research will be new basic science knowledge about the ocular surface barrier, how it is altered in disease, and mechanisms of protection by clusterin. The results will set the stage for clinical innovation.

7.项目总结/摘要 干眼症是一种常见的眼部疾病，影响数百万人。干眼症是由 老化、眼科手术或环境暴露，并且也是接触透镜佩戴的不利影响， 眼科药物症状包括疼痛、灼热、瘙痒、发红、对光敏感和其他不适。如果 如果不进行治疗，严重的病例可能会由于角膜瘢痕而导致视力丧失。这项研究的新成果 最近发表在NIH支持的期刊PLOS ONE上的一个研究小组提出了一种治疗干燥的新方法。 眼睛研究人员使用实验小鼠模型发现， 丛生蛋白选择性地结合到被干燥应激破坏的眼表屏障上， 同时也防止了进一步的伤害。丛生蛋白的已知特性表明它可以进一步保护 对抗炎症级联激活和随后的鳞状上皮化生的上游效应。的 拟议的研究将调查这种以前未被认识到的内源性保护机制。的 计划中的研究利用小鼠实验模型和眼部功能的定量测定， 表面屏障破坏，并利用小鼠遗传学。具体目标是：1）确定 clusterin嵌入眼表面糖萼的分子性质，以及它如何与所有的 或无影响; 2）记录丛生蛋白在抗蛋白水解中的作用，蛋白水解对细胞增殖能力的影响， clusterin结合，以及蛋白水解和clusterin途径之间的关系; 3）定义 内源性丛生蛋白保护途径及其在维持抗炎环境中的作用 眼表这项研究的影响将是关于眼表的新的基础科学知识 屏障，它是如何在疾病中改变的，以及丛生蛋白的保护机制。结果将为 临床创新