Role of the nerve regeneration-associated gene Sox11 in promoting corneal innervation and epithelial cell repair in dry eye

神经再生相关基因Sox11在促进干眼角膜神经支配和上皮细胞修复中的作用

• 批准号: 9767195
• 负责人: IAN D MENG
• 金额: $ 35.6万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767195
• 关键词: Affect; Afferent Neurons; Animals; Apoptosis; Attenuated; Behavior; Caliber; Cell Proliferation; Cells; Control Animal; Cornea; Data; Defect; Dependovirus; Development; Embryo; Embryonic Development; Enterobacteria phage P1 Cre recombinase; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Excision; Eye; Eye diseases; Feeling; Fiber; Film; Fluorescein; Gene Expression; Gene Targeting; Genes; Health; Histology; Hypesthesia; Immunohistochemistry; In Situ Nick-End Labeling; Knock-out; Knockout Mice; Lacrimal gland structure; Lead; Mechanics; Mediating; Morphology; Mus; Natural regeneration; Nerve; Nerve Regeneration; Neurons; Ophthalmologist; Optometrist; Pain; Pathologic; Pathology; Patients; Peripheral nerve injury; Play; Population; Process; Proteins; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; SOX11 gene; Saline; Sensory; Sensory Thresholds; Spinal Ganglia; Stains; Stimulus; Structure of trigeminal ganglion; Surface; Symptoms; System; Tissues; Transgenic Mice; Trigeminal System; Tubulin; United States; Up-Regulation; Viral Vector; Vision; Visit; activating transcription factor 3; axon growth; cell injury; corneal epithelium; eye dryness; healing; improved; in vivo; insight; knockout animal; mature animal; nerve injury; nerve supply; novel; novel therapeutics; ocular pain; overexpression; prevent; programs; release factor; repaired; response; response to injury; sham surgery; transcription factor

Dry eye disease results from an inadequate tear film on the corneal surface that can result in ocular pain and in some cases serious vision problems. Symptoms of dry eye disease are a primary reason for patient visits to ophthalmologists and optometrists in the United States, and for many sufferers treatment remains inadequate. Previous studies demonstrate a clear role for corneal primary afferent neurons in maintaining the corneal epithelium under normal conditions, presumably through the release of factors that prevent epithelial cell apoptosis and stimulate proliferation. However, the role of these sensory neurons in supporting corneal healing under pathological conditions such as dry eye remains unknown. We hypothesize that dry eye disease and its associated corneal damage initiates an injury-response program in corneal afferent neurons that involves the upregulation of nerve regeneration-associated genes, such as the transcription factor Sox11, in the trigeminal ganglion. It is proposed that upregulation of Sox11 in dry eye is critical for maintaining corneal afferent innervation and thus maintaining the trophic support required to promote corneal healing. The aims in this proposal explore the impact of Sox11 expression in the trigeminal ganglion and the role it plays in maintaining corneal afferent innervation and promoting corneal healing in dry eye. Aim 1 will examine the expression of Sox11 and its downstream gene targets in corneal afferent cell bodies of the trigeminal ganglion following induction of dry eye by lacrimal gland excision. Aim 2 will determine the role of Sox11 in maintaining corneal innervation and sensitivity in dry eye, utilizing a transgenic mouse line in which Sox11 is deleted only in small diameter sensory fibers (including corneal primary afferent neurons). The contribution of Sox11 in these neurons to corneal nerve morphology and functional sensitivity will be examined following lacrimal gland excision. Using these same mice, Aim 3 will determine how deletion of Sox11 in corneal primary afferent neurons impacts the condition of the corneal epithelium following lacrimal gland excision. Corneal fluorescein staining and epithelial cell proliferation and apoptosis will be examined. Finally, Aim 4 will utilize a viral vector to drive the overexpression Sox11 in small diameter sensory fibers, including the corneal afferent neurons, to determine if increasing expression of Sox11 in these neurons can further promote or improve corneal healing under dry eye conditions. The proposed studies will elucidate novel mechanisms that, if targeted appropriately, could simultaneously maintain corneal innervation and facilitate corneal healing in patients suffering from dry eye disease.

干眼症是由角膜表面上的泪膜不足引起的，其可导致眼部疼痛， 有些情况下严重的视力问题。干眼病的症状是患者就诊的主要原因， 美国的眼科医生和验光师，对许多患者的治疗仍然不足。 以前的研究表明，角膜初级传入神经元在维持角膜上皮细胞的功能中具有明确的作用。 在正常情况下，可能是通过释放阻止上皮细胞增殖的因子， 凋亡和刺激增殖。然而，这些感觉神经元在支持角膜愈合中的作用 在干眼症等病理条件下仍然未知。我们假设干眼症及其 相关的角膜损伤启动了角膜传入神经元的损伤反应程序， 三叉神经中神经再生相关基因的上调，如转录因子Sox 11， 神经节这表明Sox 11在干眼症中的上调对于维持角膜传入至关重要。 神经支配，从而维持促进角膜愈合所需的营养支持。这其中的目的 我们的建议是探索Sox11在三叉神经节中表达的影响，以及它在维持三叉神经节的功能中所起的作用。 角膜传入神经支配和促进干眼角膜愈合。目标1将检查 Sox 11及其下游基因在三叉神经节角膜传入胞体中的作用 通过泪腺切除诱导干眼症。目的2将确定Sox 11在维持角膜基质中的作用。 干眼的神经支配和敏感性，利用转基因小鼠系，其中Sox 11仅在小的 直径感觉纤维（包括角膜初级传入神经元）。Sox 11在这些方面的贡献 将在泪腺后检查神经元对角膜神经形态和功能敏感性 切除使用这些相同的小鼠，Aim 3将确定角膜初级传入纤维中Sox 11的缺失如何影响角膜初级传入纤维中Sox 11的表达。 神经元影响泪腺切除后角膜上皮的状况。角膜荧光素 染色和上皮细胞增殖和凋亡将被检查。最后，Aim 4将利用病毒载体 驱动小直径感觉纤维（包括角膜传入神经元）中Sox 11的过表达， 确定增加这些神经元中Sox11的表达是否可以进一步促进或改善角膜愈合 在干眼症的情况下。拟议的研究将阐明新的机制，如果靶向得当， 在维持角膜神经支配的同时， 眼疾。