Therapeutic Strategies for Repairing Optic Nerve Injury

修复视神经损伤的治疗策略

基本信息

批准号：
8749408
负责人：
SHUXIN LI
金额：
$ 35.1万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8749408
关键词：
Address Adult Apoptosis Apoptotic Axon Axotomy Blindness Caspase Cell Death Cell Survival Cells Chondroitin Sulfate Proteoglycan Cicatrix Crush Injury Development Dose Environment Failure Figs - dietary Growth In Vitro Injury Intrinsic factor Knock-out Knockout Mice LAR tyrosine phosphatase receptor Life Mediating Modeling Molecular Molecular Target Mus Natural regeneration Nerve Crush Neurons Optic Nerve Optic Nerve Injuries Optics PTEN gene Pathway interactions Patients Peptides Phosphoric Monoester Hydrolases Protein Tyrosine Phosphatase Retinal Ganglion Cells Rodent Signal Transduction Testing Therapeutic Transgenic Organisms Tumor Suppressor Genes axon growth axon regeneration base central nervous system injury combinatorial design extracellular improved in vivo inhibitor/antagonist injured mimetics novel novel strategies public health relevance receptor regenerative repaired research study

项目摘要

DESCRIPTION (provided by applicant): This is a proposal that uses novel, systemically deliverable, small inhibitory peptides to determine whether combined targeting of neuron-intrinsic and extracellular inhibitory factors markedly improves retinal ganglion cell (RGC) axon regeneration and survival after optic nerve injury (ONI). Severed optic axons fail to regenerate and ONI leads to life-long visual loss in patients. In addition to apoptotic RGC death following axotomy, both a reduced intrinsic growth capacity and an inhibitory molecular environment contribute to failure of mature CNS neurons to regenerate their axons. Studies using conditional knockout (KO) mice suggest that the tumor suppressor gene PTEN is one neuron-intrinsic factor that critically restricts the regenerative capacity of adult RGCs. Deletion of PTEN enhanced RGC axon growth and survival after ONI. Chondroitin sulfate proteoglycans (CSPGs) generated in glial scars are extrinsic factors that strongly suppress axon extension. Recently, we and other labs identified LAR and PTP¿ phosphatases as receptors that mediate CSPG inhibition. Deletion of either of them partially overcomes suppression by CSPGs and stimulates growth of injured CNS axons. Some PTPs, including LAR, can also activate caspases and induce cell apoptosis. Suppressing PTEN and CSPG signaling is very promising for promoting CNS axon regeneration, but transgenic deletion of PTEN, LAR or PTP¿ is not feasible for treating patients. We have designed small mimetic peptides to block functions of these inhibitory molecules and demonstrated their efficiency in promoting axon growth in vitro and in vivo. Because CSPG receptors appear to regulate neuronal functions via pathways different from PTEN signaling, we hypothesize that combining inhibition of PTEN and CSPG signaling promotes RGC axon regeneration and survival better than inhibiting either alone. To test this hypothesis, we will use small peptide inhibitors alone and in combinations, validating the peptide efficacy by comparison to results with KO mice available in our lab. We propose to address 3 Specific Aims by determining whether: 1) peptide blockade of PTEN promotes similar RGC axon regeneration and survival as transgenic deletion in KO mice; 2) peptide blockade of two CSPG receptors promotes greater RGC axon regeneration and survival than inhibiting one receptor; and 3) blocking both PTEN and CSPG signaling with peptides promotes greater RGC axon regeneration and survival than targeting either one alone. By simultaneously targeting neuron-intrinsic and environmental inhibitory factors with small blocking peptides, we attempt to promote axon regeneration and to reduce axotomy-induced RGC loss to greater degrees than by targeting either signal individually. Our novel strategy of administering small, systemically deliverable compounds post-injury may facilitate development of practical combinatorial therapy for optic nerve injury.

描述（由适用提供）：这是一项建议，使用新颖的，全身可传递的，小的抑制性肽来确定神经内在和细胞外抑制因子的联合靶向是否明显改善视网膜神经节细胞（RGC）轴突再生和光神经损伤后的生存率（ONI）。切断的视神经轴突无法再生，ONI导致患者终生视觉丧失。除了轴突切开术后凋亡的RGC死亡外，固有的生长能力降低和抑制性分子环境都有助于成熟的CNS神经元失败以再生其轴突。使用条件敲除（KO）小鼠的研究表明，肿瘤抑制基因PTEN是一种神经元内因子，严重限制了成年RGC的再生能力。 PTEN的缺失增强了RGC轴突的生长和ONI后的存活。神经胶质疤痕中产生的硫酸软骨蛋白蛋白聚糖（CSPG）是强烈抑制轴突延伸的外部因素。最近，我们和其他实验室将LAR和PTP磷酸酶确定为介导CSPG抑制作用的受体。其中任何一个的缺失部分克服了CSPG并刺激受伤的CNS轴突的生长。包括LAR在内的一些PTP也可以激活胱天蛋白酶并诱导细胞凋亡。抑制PTEN和CSPG信号传导对于促进CNS轴突再生非常有前途，但是PTEN，LAR或PTP？的转基因缺失对于治疗患者是不可行的。我们设计了小的模拟宠物来阻止这些抑制性分子的功能，并证明了它们在体外和体内促进轴突生长方面的效率。由于CSPG受体似乎通过不同于PTEN信号传导的途径来调节神经元功能，因此我们假设将PTEN和CSPG信号抑制结合起来促进RGC轴突再生和生存更好，而不是单独抑制任何一个。为了检验这一假设，我们将使用与我们实验室中可用的KO小鼠相比，单独和组合中的小肽抑制剂验证了肽效率。我们建议通过确定以下确定是否：1）PTEN的肽阻塞来解决3个特定目标，从而促进了与KO小鼠中类似的RGC轴突再生和与转基因缺失相似的RGC轴突再生； 2）与抑制一个受体相比，两种CSPG受体的肽阻断促进了更大的RGC轴突再生和存活。 3）用Petides阻止PTEN和CSPG信号传导比单独靶向任何一个。通过简单地靶向具有较小的阻塞宠物的神经元内和环境抑制因子，我们试图促进轴突再生并将轴切开术诱导的RGC损失降低到更大程度上，而不是单独靶向任何一个信号。我们采用损伤后进行小型，全身交付的化合物的新型策略可能有助于开发用于视神经损伤的实用组合疗法。