Clusterin at the Ocular Surface

眼表面的聚集蛋白

• 批准号: 9329433
• 负责人: M. Elizabeth Fini
• 金额: $ 51.61万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329433
• 关键词: Address; Adverse effects; Affect; Aging; Anti-Inflammatory Agents; 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。项目摘要/摘要 干眼症综合征是影响数百万人的眼睛的常见痛苦。干眼由 衰老，眼科手术或环境暴露，也是隐形眼镜磨损的不利影响，局部 眼药。症状包括疼痛，燃烧，瘙痒，发红，对光和其他不适感的敏感性。如果 未经治疗的严重病例可能导致视力损失，因此角膜疤痕。这项研究的新研究 最近出版在NIH支持的期刊PLOS One上的团队提出了一种新的方法来治疗干燥的方法 眼睛。使用实验小鼠模型，研究人员发现天然泪液被称为 簇蛋白选择性地结合了通过全或任何人的干燥应力破坏的眼表屏障 方式，同时还可以防止进一步的损害。簇蛋白的已知特性表明它可能会进一步保护 反对炎症级联激活和随后的鳞状化生的上游影响。这 拟议的研究将研究这种先前未知的内源性保护机制。这 计划的研究利用小鼠实验模型和眼睛的定量功能测定 表面屏障破坏并利用小鼠遗传学。具体目的是：1）确定 聚集蛋白插入到眼表糖卵果的分子性质，以及它如何与全面关系 或无效的效果； 2）记录簇蛋白在抗蛋白解中的作用，蛋白水解对能力的影响 用于簇蛋白结合以及蛋白水解和簇蛋白途径之间的关系； 3）定义 内源性簇蛋白保护途径及其在维持抗炎环境中的作用 眼表面。这项研究的影响将是有关眼表面的新基础科学知识 障碍，疾病的改变以及簇蛋白的保护机制。结果将为 临床创新。