Regeneration and Reconnection of Damaged Optic Nerve

描述(申请人提供)：视网膜神经节细胞(RGC)轴突再生不良是治疗眼外伤和青光眼等疾病的主要障碍。一旦视神经受损，目前还没有修复视神经的疗法。我们现在证明，利用小干扰RNA(SiRNA)调节成年视网膜节细胞中PTEN(磷酸酶和张力蛋白同源)的表达，并上调睫状神经营养因子(CNTF)和环磷酸腺苷(CAMP)，可以促进强大的视神经再生。值得注意的是，一些再生轴突成功地到达了大脑的目标-视交叉上核(SCN)，这是调节昼夜节律的主要起搏器。这项建议的总体目标是确定：i)到达SCN的轴突是否形成功能连接并诱导昼夜节律的恢复，以及ii)制定进一步促进视神经再生到中枢靶点的策略。尽管再生令人印象深刻，但并不是所有的视网膜神经元都能长距离再生轴突，许多再生轴突在视交叉处停滞不前。在目标1中，我们将结合各种策略来增强视网膜节细胞的内在生长潜力，以进一步增加再生。接下来，我们将寻找限制轴突再生进入视神经和视神经以外的因素。 交叉。最近，我们发现光感受器蛋白的过度表达可以诱导一些轴突再生。在目标2中，我们将阐明这种再生形式背后的分子机制。目前尚不清楚SCN中再生的轴突是否恢复了SCN适应明暗周期的能力，这一过程被称为昼夜光夹带。在目标3中，我们将确定到达SCN的轴突是否形成功能连接并诱导昼夜节律光携带的恢复。找出进一步增加大脑再生的方法，并确定再生的轴突是否能恢复视觉功能，这是未来的关键研究。这些研究的结果将为开发未来修复青光眼和外伤性视神经病变后变性视神经的治疗方法提供宝贵的信息。

DESCRIPTION (provided by applicant): Poor regeneration of retinal ganglion cell (RGC) axons is a major obstacle for treating ocular trauma and diseases including glaucoma. There are as yet no therapies to repair optic nerve once the damage is done. We now demonstrate that modulation of PTEN (phosphatase and tensin homolog) expression in adult RGCs using small interference RNAs (siRNA), with elevation of ciliary neurotrophic factor (CNTF) and cyclic AMP (cAMP) promotes robust optic nerve regeneration. Remarkably, some regenerating axons successfully reach a brain target, the suprachiasmatic nucleus (SCN), a master pacemaker for regulating circadian rhythms. The overall goal of this proposal is to determine; i) whether the axons that reach to the SCN form functional connections and induce recovery of circadian rhythm, and ii) develop strategies to further enhance optic nerve regeneration to the central targets. Despite impressive regeneration, not all retinal neurons regenerated their axons over long distances, and many regenerating axons stalled at the optic chiasm. In Aim 1, we will combine strategies to enhance the intrinsic growth potentials of RGCs to further increase regeneration. Next, we will look for factors that limit axon regeneration into and beyond the optic chiasm. Recently, we found that over-expression of light sensor proteins induces some axon regeneration. In Aim 2, we will elucidate the molecular mechanisms underlying this form of regeneration. It is unknown whether the regenerated axons in the SCN restore the ability of the SCN to adjust to light dark cycles, a process known as circadian photoentrainment. In Aim 3, we will determine whether the axons that reach to the SCN form functional connections and induce recovery of circadian photoentrainment. Identifying methods to further increase regeneration to brain and determining whether the regenerated axons restore visual functions represent critical future studies. Results obtained from these studies will provide invaluable information on developing future therapies to repair degenerated optic nerve after glaucoma and traumatic optic neuropathy.