Functional Restoration of the Optic Nerve After Disease or Damage

疾病或损伤后视神经的功能恢复

• 批准号: 7751235
• 负责人: Dong Feng Chen
• 金额: $ 48.41万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751235
• 关键词: Adult; Age; Animals; Appearance; Area; Astrocytes; Axon; Axotomy; Blindness; Brain; Cellular biology; Central Nervous System Diseases; Cicatrix; Critiques; Data; Development; Disease; Event; Failure; Future; Glaucoma; Goals; Human; Injury; Ipsilateral; Knockout Mice; Laboratories; Lead; Light; Maps; Mediating; Methods; Modeling; Multiple Sclerosis; Mus; Myelin; Natural regeneration; Nerve; Neuroanatomy; Neurologic; Neurons; Optic Nerve; Optic Nerve Injuries; Optic Neuritis; Outcome; Principal Investigator; Published Comment; Research; Retinal Degeneration; Retinal Ganglion Cells; Role; Side; Signal Transduction; Suggestion; Synapses; Testing; Time; Transplantation; Trauma; Vision; Visual; Visual evoked cortical potential; axon regeneration; behavior test; functional restoration; genetic technology; improved; mature animal; novel strategies; optic nerve disorder; optic nerve regeneration; postnatal; programs; relating to nervous system; repaired; research study; response; restoration; synaptogenesis; treatment strategy

DESCRIPTION (provided by applicant): The long-term objectives of this research plan are to combine approaches of neuroanatomy, cellular biology and mouse behavior tests to probe for mechanisms regulating optic nerve regeneration and restoring vision after injury or diseases. Optic nerve damage is a major feature of several blinding diseases, such as glaucoma, optic neuropathy, and trauma. Finding ways to rescue retinal ganglion cells from degeneration and to promote optic nerve regrowth are crucial to the development of efficacious treatment for these conditions. Previously, using the established model of optic nerve axotomy and mouse genetic technology, we identified two barriers to optic nerve regeneration the loss of Bcl-2 expression and maturation of astrocytes and their acquisition of the ability to form glial scars. By eliminating these two barriers demonstrated for the first time successful optic nerve re-elongation into the brain targets, up to postnatal day 14 (P14) in mice. Interestingly, regenerating axons in the postnatal mice entered the wrong (ipsilateral) side of the brain and innervated the visual targets in there. However, the regeneration fails consistently if the injury is incurred after P14, suggestion development of additional barriers to nerve regrowth at this age. The key remaining questions are: (1) what is the additional barrier to optic nerve regeneration that is developed after P14 and whether successful regeneration of the severed optic nerve can be achieved in the adult, and (2) whether regenerated axons are capable of establishing a topographic map and functional synapses with target neurons and in turn restoring vision. Recent studies in my laboratory implicate that appearance of the third and likely the last barrier to optic nerve regeneration is related to the development of CNS myelin. We hypothesize that the three barriers to optic nerve regeneration include the loss of Bcl-2 expression by retinal ganglion cells, development of glial scars, and appearance of CNS myelin; simultaneous elimination of the three barriers will allow optic nerve regeneration and restoration of vision in the adult. The three specific aims of this research plan includes: (1) To determine if simultaneous eliminating the three barriers to retinal ganglion axonal regrowth will enable optic nerve regeneration in the adult. (2) To determine a role for EphB1 in directing the ipsilateralization projection of retinal ganglion cell axons during regeneration, using the model of EphB1 knockout mice. (3) To investigate whether regenerated RGC axons are capable of establishing topographically ordered functional connections that can lead to vision restoration, using neuroanatomy, visual evoked potential, and animal behavioral tests. The results of this study may lead to a novel strategy for using neural transplantation to treat blindness and other CNS diseases. Project Narrative: Failure of optic nerve injury to be repaired is a major feature of several blinding diseases, including glaucoma, optic neuritis, and multiple sclerosis, as well as trauma. Our present research plan is proposed to identify and alleviate all barriers to optic nerve regeneration. The results of these proposed studies will open the door for future development of treatment strategies for optic nerve damage after disease or injury.

描述（由申请人提供）：本研究计划的长期目标是结合神经解剖学、细胞生物学和小鼠行为学试验的联合收割机方法，探索视神经损伤或疾病后再生和恢复视力的调节机制。视神经损伤是几种致盲疾病的主要特征，如青光眼、视神经病变和创伤。寻找方法来拯救视网膜神经节细胞从变性和促进视神经再生是至关重要的发展有效的治疗这些条件。在此之前，利用建立的视神经轴突切断模型和小鼠遗传技术，我们确定了视神经再生的两个障碍，即Bcl-2表达和星形胶质细胞成熟的丧失以及它们形成胶质瘢痕的能力的获得。通过消除这两个障碍，首次证明了小鼠在出生后第14天（P14）成功地将视神经重新延伸到大脑靶点。有趣的是，出生后小鼠的再生轴突进入了错误的（同侧）大脑，并支配了那里的视觉目标。然而，如果损伤发生在P14之后，再生总是失败，这表明在这个年龄段神经再生的额外障碍的发展。剩下的关键问题是：（1）在P14之后发展的视神经再生的额外障碍是什么，以及在成人中是否可以实现切断的视神经的成功再生，以及（2）再生的轴突是否能够与靶神经元建立地形图和功能性突触，从而恢复视力。我实验室最近的研究表明，视神经再生的第三个也可能是最后一个障碍的出现与CNS髓鞘的发育有关。我们假设视神经再生的三个障碍包括视网膜神经节细胞Bcl-2表达的丧失、胶质瘢痕的发展和CNS髓鞘的出现;同时消除这三个障碍将允许视神经再生和视力恢复。本研究计划的三个具体目标包括：（1）确定同时消除视网膜神经节轴突再生的三个障碍是否能够使成人视神经再生。(2)使用EphB 1敲除小鼠模型，确定EphB 1在再生期间指导视网膜神经节细胞轴突的同侧投射中的作用。(3)研究再生的RGC轴突是否能够建立拓扑有序的功能连接，可以导致视力恢复，使用神经解剖学，视觉诱发电位和动物行为测试。这项研究的结果可能会导致一种新的策略，使用神经移植治疗失明和其他中枢神经系统疾病。 项目叙述：视神经损伤无法修复是几种致盲疾病的主要特征，包括青光眼、视神经炎和多发性硬化以及创伤。我们目前的研究计划旨在识别和缓解视神经再生的所有障碍。这些研究的结果将为疾病或损伤后视神经损伤的治疗策略的未来发展打开大门。

项目成果

Mobilizing endogenous stem cells for retinal repair.

• DOI: 10.1016/j.trsl.2013.11.011
• 发表时间: 2014-04
• 期刊: Translational research : the journal of laboratory and clinical medicine
• 作者: Yu H;Vu TH;Cho KS;Guo C;Chen DF
• 通讯作者: Chen DF

Impact of Storage Temperature on the Expression of Cell Survival Genes in Cultured ARPE-19 Cells.

储存温度对培养 ARPE-19 细胞中细胞存活基因表达的影响。

• DOI: 10.3109/02713683.2016.1145236
• 发表时间: 2017
• 期刊: Current eye research
• 影响因子: 2
• 作者: Pasovic,Lara;Eidet,JonR;Olstad,OleK;Chen,DongF;Lyberg,Torstein;Utheim,TorP
• 通讯作者: Utheim,TorP

Ephrin-A3 suppresses Wnt signaling to control retinal stem cell potency.

• DOI: 10.1002/stem.1283
• 发表时间: 2013-02
• 期刊: STEM CELLS
• 影响因子: 5.2
• 作者: Fang, Yuan;Cho, Kin-Sang;Tchedre, Kissaou;Lee, Seung Woo;Guo, Chenying;Kinouchi, Hikaru;Fried, Shelley;Sun, Xinghuai;Chen, Dong Feng
• 通讯作者: Chen, Dong Feng