Regeneration and Reconnection of Damaged Optic Nerve

受损视神经的再生和重新连接

• 批准号: 8601703
• 负责人: KEVIN Kyung PARK
• 金额: $ 34.7万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601703
• 关键词: Adult; Aftercare; Axon; Bilateral; Brain; Ciliary Neurotrophic Factor; Circadian Rhythms; Crush Injury; Cyclic AMP; Data; Dependovirus; Disease; Distal; Ectopic Expression; Electron Microscopy; Embryo; Eye; Future; Glaucoma; Goals; Grant; Green Fluorescent Proteins; Growth; Image; Immunohistochemistry; Injury; Label; Lateral Geniculate Body; Light; Methods; Modeling; Molecular; Mus; Natural regeneration; Nerve Crush; Optic Chiasm; Optic Nerve; Optic Nerve Injuries; Optic Neuritis; PTEN gene; Pacemakers; Population; Process; Proteins; RNA Interference; Recovery; Recovery of Function; Reporter; Retinal Ganglion Cells; Route; Synapses; Testing; Time; Transgenic Mice; Trauma; Travel; Vision; axon growth; axon regeneration; axonal pathfinding; enhancing factor; functional restoration; improved; melanopsin; novel; optic nerve regeneration; overexpression; photoactivation; programs; public health relevance; repaired; retinal neuron; sensor; superior colliculus Corpora quadrigemina; suprachiasmatic nucleus

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.

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青光眼等疾病的主要障碍。目前还没有治疗视神经损伤的方法。我们现在证明，使用小干扰rna （siRNA）调节PTEN（磷酸酶和紧张素同源物）在成人RGCs中的表达，增加睫状神经营养因子（CNTF）和环AMP (cAMP)，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一个目标，即视交叉上核（SCN），这是调节昼夜节律的主要起搏器。本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，ii)制定进一步增强视神经向中枢目标再生的策略。尽管再生能力令人印象深刻，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，我们将结合策略来增强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越视神经的因素