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Protective Lipid Circuits in Corneal Injury and Disease

角膜损伤和疾病中的保护性脂质回路

基本信息

批准号：
7250153
负责人：
KARSTEN GRONERT
金额：
$ 7.86万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-01 至 2007-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7250153
关键词：
Acceleration Address Affect Anti-Inflammatory Agents Anti-inflammatory Appendix Arachidonate 15-Lipoxygenase Autacoids Blindness Blood Brain Cicatrix Class Clinical Research Cornea Corneal Injury Cytochrome P450 Dermal Dietary Supplementation Disease Docosahexaenoic Acids Edema Eicosanoids Enzymes Epithelial Equilibrium Exhibits Exudate Eye Eye Infections Fatty Acids Fetal Development Generations Genes Goals Healed Host Defense Impaired wound healing Inflammation Inflammatory Inflammatory Response Injury Irritants Keratitis Lead Leukotrienes Lipids Lipoxin Receptors Lipoxins Maize Mediator of activation protein Microbe Molecular Biology Molecular Mechanisms of Action Mus Omega-3 Fatty Acids Pathway interactions Peptides Phenotype Platelet Activating Factor Prostaglandins Research Personnel Resolution Role Route Series Signal Transduction Site Surface Testing Therapeutic Topical application Transgenic Mice Ulcer Vascular Endothelial Growth Factors Vision Visual Acuity Work Wound Healing Zea mays angiogen doxorubicin/fluorouracil/melphalan protocol genetic manipulation healing in vivo interest lipid mediator lipoxin A4 neovascularization novel novel therapeutics programs receptor response toe corn

项目摘要

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.

产品说明：角膜的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。我们对控制自然消退的内源性机制的理解是有限的，特别是在眼睛中;破坏促炎回路或促进上皮愈合的途径仍有待确定。我们已经发现了一类新的抗炎脂质autacoids（resolvins），它们由omega-3脂肪酸产生，并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充分记载的抗炎脂质介质脂氧素（LX）相同。这些脂质回路存在于角膜中，更重要的是，LXA 4或17 S-消退素的治疗应用抑制炎症并促进小鼠角膜中的伤口愈合。因此，我们假设角膜损伤诱导抗炎脂质介质，即脂氧素和DHA衍生的17 S-消退素的形成，并且这些保护性脂质回路的饮食或治疗放大促进伤口愈合并限制角膜损伤的后遗症。为了确定脂质自分泌物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特定的目标：I）确定抗炎脂质介质，即脂氧素和DHA衍生的17 S-消退素，作为炎症修复反应的一部分形成; II）确定17 S-消退素途径的ω-3饮食放大或LXA 4或17 S-消退素的直接局部应用是否加速角膜中的炎症消退和伤口愈合; III）证明LXA 4受体的表达或用于形成17 S-消退素和脂氧素的生物合成途径是限制角膜损伤的决定因素。这项建议的结果将确定内源性机制，限制角膜炎症和促进上皮伤口愈合，因此，可能是至关重要的，以保持角膜透明度。此外，它们可能提供一种新的替代方法来治疗角膜损伤，即，内源性保护脂质回路的放大。