Lipid Mediators in Corneal Nerve Regeneration

角膜神经再生中的脂质介质

• 批准号: 8012588
• 负责人: Haydee E.P. Bazan
• 金额: $ 0.87万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012588
• 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 Proteins; Genetic Models; Growth; Health; Human; Hydroxyeicosatetraenoic Acids; Hypesthesia; Image; In Vitro; Incidence; Infection; Injury; Keratitis; Knockout Mice; LOX gene; 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; public health relevance; 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，是用于矫正视力的最常见手术之一（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。角膜密集地受感觉神经支配，感觉神经对角膜上皮施加营养影响。对这些神经的损伤导致并发症，如角膜感觉减退和干眼以及伤口愈合减少（2-4），这导致透明度和视力丧失。鉴于这一问题的频率和重要性，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这些手术后受损的角膜神经再生中所起作用的创新理解来降低术后并发症的发生率。我们将确定色素上皮衍生因子（PEDF）和二十二碳六烯酸（DHA）治疗增加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脂氧合酶（12/15-LOX），增加神经保护素D1（NPD 1）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，并降低干眼的发病率。我们预测NPD 1调节角膜损伤后细胞存活信号，是神经再生的主要介质。我们将使用体内角膜手术动物模型，包括遗传模型（12/15-LOX基因敲除小鼠），体内触觉测量和共聚焦显微镜，液相色谱-质谱脂质组学分析，细胞和分子方法来测试假设。我们的具体目的是验证以下假设：（1）角膜手术后PEDF增加，并刺激12/15-LOX的表达，进而合成NPD 1和AA衍生的介质：（2）12/15-LOX产物选择性地诱导角膜损伤后的神经发生;（3）NPD 1在角膜上皮细胞中作为神经保护剂，允许更好的伤口愈合并降低角膜手术后干眼的发生率。我们的研究目标是与角膜神经损伤产生的并发症的理解和治疗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。公共卫生关系：该项目提出的研究重点是通过提供对损伤后脂质细胞信号传导机制作用的创新理解，增强角膜手术后受损角膜神经的再生，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产生的并发症相关的神经再生机制。我们的新方法将确定屈光手术后神经营养性角膜炎和干眼的潜在治疗药物，从而对如何修复或预防这些手术引起的损伤产生新的见解。