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; 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.

干眼病是由于角膜表面上的撕裂膜不足而导致的，可能导致眼部疼痛和 在某些情况下，严重的视力问题。干眼症的症状是患者访问的主要原因 美国的眼科医生和验光师，对于许多患者而言，治疗仍然不足。 先前的研究表明，角膜原发性传入神经元在维持角膜中的作用明确 正常条件下的上皮，大概是通过释放预防上皮细胞的因素 凋亡并刺激增殖。但是，这些感觉神经元在支撑角膜愈合中的作用 在病理状态下，如干眼仍然未知。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中的损伤反应计划，涉及 神经再生相关基因的上调（例如转录因子SOX11） 神经节。有人提出，干眼症中Sox11的上调对于维持角膜传入至关重要 神经，从而维持促进角膜愈合所需的营养支持。目的 提案探讨Sox11表达在三叉神经节中的影响及其在维持的作用 角膜传入神经和干眼症的角膜愈合。 AIM 1将检查 Sox11及其下游基因靶标在三叉神经节的角膜传统细胞体中 通过泪腺切除诱导干眼。 AIM 2将确定Sox11在维持角膜中的作用 干眼症的神经和灵敏度，利用转基因小鼠系列，其中Sox11仅在小中删除 直径的感觉纤维（包括角膜初级传入神经元）。这些在这些中的贡献 在泪腺后将检查神经元至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将决定角膜初级传入中Sox11的缺失 神经元影响泪腺切除后角膜上皮的状况。角膜荧光素 将检查染色和上皮细胞增殖和凋亡。最后，AIM 4将使用病毒载体 在小直径的感觉纤维中，将过表达的Sox11（包括角膜传入神经元）驱动到 确定这些神经元中Sox11的表达是否增加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机制，如果适当针对的， 可以同时维持角膜神经支配并促进患有干燥患者的角膜愈合 眼病。