Lipid Mediators in Corneal Nerve Regeneration

角膜神经再生中的脂质介质

• 批准号: 8267934
• 负责人: Haydee E.P. Bazan
• 金额: $ 5.75万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267934
• 关键词: Abbreviations; Acids; Animal Model; Animals; Anterior; Apoptosis; Apoptotic; Arachidonate 15-Lipoxygenase; Arachidonic Acids; Area; Calcitonin Gene-Related Peptide; Cell Culture Techniques; Cell Survival; Cell membrane; Cells; Confocal Microscopy; Contact Lenses; Cornea; Corneal Injury; Dendrites; Diabetes Mellitus; Docosahexaenoic Acids; Epithelial; Epithelial Cells; Fatty Acids; Frequencies; Gene Expression; Genetic Models; Growth; Health; Human; Hydroxyeicosatetraenoic Acids; Hypesthesia; Image; In Vitro; Incidence; Infection; Injury; Keratitis; Knockout Mice; Laboratories; Lamellar Keratoplasty; Laser In Situ Keratomileusis; Lipids; Measures; Mechanics; Mediator of activation protein; Microscope; Modeling; Molecular; Myofibroblast; Natural regeneration; Nerve; Nerve Regeneration; Neurons; Neuropeptides; Neuroprotective Agents; Omega-3 Fatty Acids; Operative Surgical Procedures; Oryctolagus cuniculus; Penetrating Keratoplasty; Phospholipase A2; Photorefractive Keratectomy; Pigments; Play; Postoperative Complications; Procedures; Proteins; Research; Research Project Grants; Retinal; Role; Sampling; Signal Transduction; Source; Stromal Cells; Structure of trigeminal ganglion; Substance P; Surgical Injuries; Testing; Therapeutic Agents; Time; Vision; Wound Healing; afferent nerve; autocrine; base; brain cell; corneal epithelium; corneal surgery; eye dryness; improved; in vivo; innovation; insight; lipid mediator; lipoxin A4; liquid chromatography mass spectrometry; migration; nerve injury; neurogenesis; neuroprotectin D1; neuroprotection; novel strategies; paracrine; prevent; pro-apoptotic protein; protein expression; repaired; stem; tandem mass spectrometry

DESCRIPTION (provided by applicant): Corneal surgery, including refractive surgery, is one of the most frequent procedures used to correct vision (1). It is estimated that more than 17 million people worldwide have had some type of corneal surgery. The cornea is densely innervated with sensory nerves that exert a trophic influence on the corneal epithelium. Damage to these nerves leads to complications such as corneal hypoesthesia and dry eye as well as decreased wound healing (2-4), which results in loss of transparency and vision. Given the frequency and significance of this problem, this research project focuses on decreasing the incidence of postoperative complications by providing innovative understanding of the role lipid cell signaling mechanisms play after injury in enhancing the regeneration of corneal nerves damaged after these procedures. We will define the mechanism by which treatment with pigment epithelial derived factor (PEDF) and docosahexanoic acid (DHA) increase the regeneration of corneal nerves. Our central hypothesis is that PEDF activates a lipid cell signaling mechanism that stimulates 12/15 lipoxygeneases (12/15-LOX), increasing the synthesis of neuroprotectin D1 (NPD1) and arachidonic acid (AA) derived messengers involved in neuroprotection of corneal epithelial cells and nerve regeneration, and decreasing the incidence of dry eye. We predict that NPD1 modulates cell survival signaling after corneal injury and is the main mediator of nerve regeneration. We will test the hypothesis using an in vivo corneal surgery animal model including a genetic model (12/15-LOX knockout mice); in vivo esthesiometry and confocal microscopy; liquid chromatography-mass spectrometry lipidomic analysis; and cellular and molecular approaches. Our specific aims are to test the hypothesis that: (1) PEDF increases after corneal surgery and stimulates the expression of 12/15-LOX, which in turn synthesizes NPD1 and AA derived mediators; (2) 12/15-LOX products selectively induce neurogenesis after corneal injury; (3) NPD1 acts as a neuroprotective agent in corneal epithelial cells, allowing for better wound healing and decreasing the incidence of dry eye after corneal surgery. Our studies target mechanisms of neuroregeneration relevant for the understanding and treatment of complications generated by corneal nerve damage. Our innovative approach defines potential therapeutic agents for neurotrophic keratitis and dry eye after refractive surgery. PUBLIC HEALTH RELEVANCE: The research proposed in this project focuses on enhancing the regeneration of corneal nerves damaged after corneal surgery procedures to decrease the incidence of postoperative complications by providing innovative understanding of the role lipid cell signaling mechanisms play after injury. The proposed studies target mechanisms of neuroregeneration relevant to understanding and treating complications generated by corneal nerve damage. Our novel approach will define potential therapeutic agents for neurotrophic keratitis and dry eye after refractive surgery, yielding new insights into how injuries stemming from these procedures can be repaired or prevented.

描述（由申请人提供）：角膜手术，包括屈光手术，是矫正视力最常用的手术之一 (1)。据估计，全世界有超过 1700 万人接受过某种类型的角膜手术。角膜由感觉神经密集支配，对角膜上皮产生营养影响。这些神经受损会导致角膜感觉减退和干眼等并发症以及伤口愈合速度下降 (2-4)，从而导致透明度和视力丧失。考虑到这个问题的发生频率和重要性，该研究项目的重点是通过提供对损伤后脂质细胞信号传导机制在增强手术后受损角膜神经再生方面所发挥的作用的创新理解，来降低术后并发症的发生率。我们将明确色素上皮衍生因子 (PEDF) 和二十二碳六烯酸 (DHA) 治疗促进角膜神经再生的机制。我们的中心假设是，PEDF 激活脂质细胞信号传导机制，刺激 12/15 脂氧化酶 (12/15-LOX)，增加神经保护素 D1 (NPD1) 和花生四烯酸 (AA) 衍生信使的合成，参与角膜上皮细胞的神经保护和神经再生，并降低干眼症的发生率。我们预测 NPD1 调节角膜损伤后的细胞存活信号，并且是神经再生的主要介质。我们将使用包括遗传模型（12/15-LOX 基因敲除小鼠）在内的体内角膜手术动物模型来检验这一假设；体内美学和共焦显微镜；液相色谱-质谱脂质组学分析；以及细胞和分子方法。我们的具体目标是检验以下假设：（1）角膜手术后 PEDF 增加并刺激 12/15-LOX 的表达，进而合成 NPD1 和 AA 衍生介质； (2) 12/15-LOX产品选择性诱导角膜损伤后的神经发生； (3) NPD1在角膜上皮细胞中充当神经保护剂，使伤口更好地愈合并降低角膜手术后干眼症的发生率。我们的研究目标是与理解和治疗角膜神经损伤引起的并发症相关的神经再生机制。我们的创新方法定义了屈光手术后神经营养性角膜炎和干眼症的潜在治疗药物。公共健康相关性：该项目提出的研究重点是通过对损伤后脂质细胞信号传导机制的作用提供创新的理解，增强角膜手术后受损的角膜神经的再生，以降低术后并发症的发生率。拟议的研究针对与理解和治疗角膜神经损伤引起的并发症相关的神经再生机制。我们的新方法将定义屈光手术后神经营养性角膜炎和干眼症的潜在治疗药物，从而为如何修复或预防这些手术引起的损伤提供新的见解。