Lipid Mediators in Corneal Nerve Regeneration

角膜神经再生中的脂质介质

基本信息

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
项目类别：
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

项目摘要

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，包括折射手术，是用于纠正视力的最常见程序之一（1）。据估计，全世界有超过1700万人进行了某种类型的角膜手术。角膜被感官神经密集地支配，对角膜上皮产生营养影响。这些神经的损害会导致并发症，例如角膜低血压和干眼症以及伤口愈合减少（2-4），从而导致透明度和视力的丧失。鉴于该问题的频率和意义，该研究项目的重点是通过对脂质细胞信号机制的作用进行创新的理解来降低术后并发症的发生率，从而在增强这些手术后受损的角膜神经的再生时发挥了作用。我们将定义用色素上皮衍生因子（PEDF）和Docosahexanoic Acid（DHA）增加角膜神经再生的机制。我们的中心假设是，PEDF激活了一种刺激12/15 lipoxygeneases（12/15-LOX）的脂质细胞信号传导机制，从而增加了神经保护素D1（NPD1）和蛛网膜酸（AA）的合成，涉及涉及脑膜细胞和Nective Remenderial Enevere dryservensive reveriserians and neverever thevere dryserve remensery remensery reveriseration的神经保护作用。我们预测NPD1会调节角膜损伤后的细胞存活信号传导，并且是神经再生的主要介体。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））检验假设；体内估计法和共聚焦显微镜；液相色谱 - 质谱法脂肪态分析；以及细胞和分子方法。我们的具体目的是检验以下假设：（1）PEDF在角膜手术后增加并刺激12/15-LOX的表达，进而综合NPD1和AA衍生的介体；（2）12/15-lox产物有选择地诱导角膜损伤后神经发生；（3）NPD1在角膜上皮细胞中充当神经保护剂，从而可以更好地伤口愈合并降低角膜手术后干眼的发生率。我们的研究针对神经变化的机制，与了解和治疗角膜神经损伤产生的并发症有关。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的潜在治疗剂。公共卫生相关性：该项目中提出的研究重点是增强角膜手术手术后受损的角膜神经的再生，以减少术后并发症的发生率，从而降低术后脂质细胞信号机制的创新理解。拟议的研究针对与角膜神经损伤产生的理解和治疗并发症相关的神经变化的机制。我们的新方法将定义对神经营养性角膜炎和屈光手术后干眼症的潜在治疗剂，从而对如何修复或预防这些手术造成的伤害产生新的见解。