Protective Lipid Circuits in Corneal Injury and Disease

角膜损伤和疾病中的保护性脂质回路

• 批准号: 7112253
• 负责人: KARSTEN GRONERT
• 金额: $ 38.08万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7112253
• 关键词: cornea; diet therapy; dietary lipid; eicosanoids; enzyme linked immunosorbent assay; eye injury; gene targeting; genetically modified animals; high performance liquid chromatography; inflammation; laboratory mouse; lipids; mass spectrometry; omega 3 fatty acid; receptor expression; wound healing

DESCRIPTION: Excessive inflammation or disordered wound repair in the cornea significantly impairs vision or ends in blindness, affecting millions of people worldwide. Our understanding of endogenous mechanisms that govern the natural resolution is limited, especially in the eye; pathways that disrupt pro-inflammatory circuits or promote epithelial healing remain to be identified. We have uncovered a novel class of anti-inflammatory lipid autacoids (resolvins) that are generated from omega-3 fatty acids and inhibit cardinal signs of inflammation. Their molecular mechanisms of action and routes of formation are shared with the well-documented anti-inflammatory lipid mediators, lipoxins (LX). These lipid circuits are present in the cornea and, more significantly, therapeutic applications of LXA4 or 17S-resolvins inhibit inflammation and promote wound healing in mouse corneas. Hence, we hypothesize that corneal injury induces formation of anti-inflammatory lipid mediators, namely, lipoxins and DHA-derived 17S-resolvins, and that dietary or therapeutic amplification of these protective lipid circuits promotes wound healing and limits the sequelae of corneal injury. To establish a role for lipid autacoids in limiting corneal injury, we will employ an approach of lipid analysis, molecular biology and in vivo genetic manipulation to address three specific AIMS: I) establish that anti-inflammatory lipid mediators, namely lipoxins and DHA-derived 17S-resolvins, are formed as part of the inflammatory reparative response; II) determine if omega-3 dietary amplification of the 17S-resolvin pathway or direct topical application of LXA4 or 17S-resolvin accelerates inflammatory resolution and wound healing in the cornea; III) demonstrate that expression of the LXA4 receptor or biosynthetic pathways for the formation of 17S-resolvins and lipoxins is a determinant for limiting corneal damage. Results of this proposal will identify endogenous mechanisms that limit corneal inflammation and promote epithelial wound healing and, therefore, may be critical to preserving corneal transparency. Moreover, they may provide a novel alternative approach to treating corneal injury, namely, the amplification of endogenous protective lipid circuits.

角膜过度炎症或伤口修复紊乱会严重损害视力或导致失明，影响全球数百万人。我们对控制自然分辨率的内源性机制的理解是有限的，尤其是在眼睛方面；破坏促炎回路或促进上皮愈合的途径仍有待确定。我们发现了一种新型的抗炎脂质类抗炎素（溶解素），它是由omega-3脂肪酸产生的，可以抑制炎症的主要迹象。它们的分子作用机制和形成途径与文献记载的抗炎脂质介质脂毒素（lipoxins， LX）相同。这些脂质回路存在于角膜中，更重要的是，LXA4或17S-resolvins的治疗应用抑制了小鼠角膜的炎症并促进了伤口愈合。因此，我们假设角膜损伤诱导抗炎脂质介质的形成，即脂毒素和dha衍生的17s -溶解蛋白，并且饮食或治疗放大这些保护性脂质回路促进伤口愈合并限制角膜损伤的后遗症。