Regeneration and Reconnection of Damaged Optic Nerve

描述（由申请人提供）：视网膜神经节细胞（RGC）轴突再生不良是治疗眼外伤和包括青光眼在内的疾病的主要障碍。目前还没有治疗方法来修复视神经损伤。我们现在证明，使用小干扰RNA（siRNA）调节成人RGCs中的PTEN（磷酸酶和张力蛋白同源物）表达，并升高睫状神经营养因子（CNTF）和环磷酸腺苷（cAMP），可促进强大的视神经再生。值得注意的是，一些再生的轴突成功地到达了大脑的目标，视交叉上核（SCN），一个调节昼夜节律的主起搏器。该提案的总体目标是确定：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）开发进一步增强视神经再生到中枢目标的策略。尽管令人印象深刻的再生，并不是所有的视网膜神经元再生轴突长距离，许多再生轴突停滞在视交叉。在目标1中，我们将联合收割机策略，以提高RGCs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和超出光学部分的因素 交叉最近，我们发现过表达的光传感器蛋白诱导一些轴突再生。在目标2中，我们将阐明这种再生形式的分子机制。尚不清楚SCN中再生的轴突是否恢复SCN适应明暗周期的能力，这一过程称为昼夜光夹带。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光夹带的恢复。确定进一步增加大脑再生的方法并确定再生的轴突是否恢复视觉功能是未来研究的关键。从这些研究中获得的结果将为开发未来的治疗方法以修复青光眼和外伤性视神经病变后的变性视神经提供宝贵的信息。

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.