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

干眼症是由于角膜表面泪膜不充分而引起的眼痛和干眼症。 有些情况下会出现严重的视力问题。干眼症的症状是患者去看医生的主要原因 眼科医生和验光师在美国，对许多患者来说，治疗仍然不够。 以前的研究表明，角膜初级传入神经元在维持角膜功能中起着明确的作用。 正常情况下的上皮，可能是通过释放阻止上皮细胞的因子来实现的 促进细胞凋亡，刺激细胞增殖。然而，这些感觉神经元在支持角膜愈合方面的作用 在诸如干眼等病理情况下，这种情况仍不清楚。我们假设干眼病及其 相关的角膜损伤在角膜传入神经元中启动损伤反应程序，涉及 神经再生相关基因，如转录因子sox11在三叉神经中高表达 神经节。我们认为干眼中sox11的表达上调是维持角膜传入的关键。 神经支配，从而维持促进角膜愈合所需的营养支持。这样做的目的是 研究Sox11在三叉神经节表达的影响及其在维持三叉神经节中的作用 干眼症的角膜传入神经和促进角膜愈合。目标1将检查以下内容的表达 SOX11及其下游基因在三叉神经节角膜传入细胞体中的表达 泪腺切除诱发干眼症。目标2将确定sox11在维持角膜中的作用 干眼的神经支配和敏感性，利用SOX11仅在小范围内缺失的转基因小鼠 感觉纤维直径(包括角膜初级传入神经元)。Sox11在这些方面的贡献 泪腺后将检查神经元对角膜神经的形态和功能敏感性 切除。利用这些相同的小鼠，Aim 3将确定sox11在角膜初级传入中的缺失 神经元影响泪腺切除后角膜上皮的状况。角膜荧光素 染色和上皮细胞的增殖和凋亡将被检测。最后，Aim 4将利用病毒载体 为了驱动包括角膜传入神经元在内的小直径感觉纤维中sox11的过表达， 确定在这些神经元中增加sox11的表达是否可以进一步促进或改善角膜愈合 在干眼的情况下。拟议的研究将阐明新的机制，如果目标适当， 可以同时维持角膜神经支配和促进干燥症患者的角膜愈合 眼疾。

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.