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.

干眼症是由于角膜表面的泪膜不充分而引起的，可导致眼睛疼痛和疼痛