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: 6965915
• 负责人: KARSTEN GRONERT
• 金额: $ 39万
• 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/6965915
• 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.

描述：角膜中过度的炎症或伤口无序修复会大大损害视力或失明，影响全球数百万的人。我们对控制自然解决方案的内源性机制的理解是有限的，尤其是在眼中。破坏促炎回路或促进上皮愈合的途径仍有待确定。我们发现了一类新型的抗炎脂质自闭症（Resolvins），这些脂质体是由omega-3脂肪酸产生的，并抑制了炎症的基本迹象。 它们的分子作用机理和形成途径与有据可查的抗炎脂质介质脂毒素（LX）共享。这些脂质电路存在于角膜中，更明显地，LXA4或17S-溶质剂的治疗应用抑制炎症并促进小鼠角膜中的伤口愈合。因此，我们假设角膜损伤会诱导抗炎脂质介质的形成，即脂氧蛋白和DHA衍生的17s溶质剂，以及这些保护性脂质电路的饮食或治疗性扩增可促进伤口愈合，并促进毛层损伤的pecelae。 为了确定脂质自载体在限制角膜损伤中的作用，我们将采用脂质分析，分子生物学和体内遗传操作的方法来解决三个具体目的：i）确定抗炎性脂质介质，即脂肪毒素和DHA衍生的17S-氧化剂，是一种发音的响应，是一种易发的反应； ii）确定Omega-3 17S-溶质途径的饮食扩增或直接局部应用LXA4或17S-溶质剂会加速炎症分辨率和角膜中的伤口愈合； iii）证明，形成17S-溶质和脂氧蛋白的LXA4受体或生物合成途径是限制角膜损伤的决定因素。 该建议的结果将确定限制角膜炎症并促进上皮伤口愈合的内源性机制，因此对于保持角膜透明度至关重要。此外，它们可以提供一种新型的治疗角膜损伤的方法，即内源性保护性脂质电路的扩增。