Genome-Wide Discovery and Translational Research for Neural Repair

总结 脊髓损伤（SCI）后会发生破坏性和持续性的神经功能缺损，尽管存活率接近100%。 所有神经元残疾的主要原因是轴突切断造成的网络断开。回收 一些运动将足以使患者在轮椅转移中获得一定程度的独立性， 肠道和膀胱管理以及运动。今天，对于30万人来说， 在美国有120万SCI患者。 中枢神经系统成年哺乳动物的中枢神经系统，与哺乳动物的外周神经系统或神经系统相比， 系统的其他生物体，具有非常有限的能力轴突再生。我们的轴突生长研究 包括Nogo和Nogo受体（NgR 1）的发现。我们证明了它们在阻止轴突生长中的作用， 发芽、再生和损伤后的恢复。我们已经证明，NgR 1（310）-Fc对于 从SCI中恢复，即使在损伤后几个月开始治疗。它正在开发用于人类SCI 审判现在。 虽然已经确定了限制轴突再生的特定因素，如NgR 1，但它们提供了一种新的方法。 对成年哺乳动物中枢神经系统再生不良的不完全解释。我们完成了一个全基因组的shRNA， 筛选限制哺乳动物CNS轴突修复的内源性基因。该方法的有效性是 通过在磷酸酶的初步筛选中鉴定INPP 5 F为限制神经修复的基因来证明。 一种细胞途径是哺乳动物筛选中生物信息学上最丰富的基因组， 调节线虫的再生。这一途径的相关性将在临床前模型中进行测试， 创伤性脊髓损伤将研究基因缺失菌株和药理学抑制，以提供经验证的 未来治疗发展的途径。这一发现对小说的发展具有重要的现实意义 SCI的治疗

SUMMARY Devastating and persistent neurological deficits occur after Spinal Cord Injury (SCI), despite survival of nearly all neurons. The primary cause of disability is disconnection of networks by axon transection. Recovery of some movement would be adequate for patients to gain a level of independence in wheel chair transfers, bowel and bladder management, and locomotion. Today, there is no approved medical therapy for the 300,000 to 1,200,000 individuals in the USA with SCI. The CNS of adult mammals, as compared to the peripheral nervous system of mammals or the nervous system of other organisms, has extremely limited capacity for axonal regeneration. Our axonal growth studies included discovery of Nogo and Nogo Receptor (NgR1). We demonstrated their role in preventing axonal sprouting, regeneration and recovery after injury. We have demonstrated that NgR1(310)-Fc is efficacious for recovery from SCI, even when treatment starts months after damage. It is being developed for human SCI trials now. While specific factors, such as NgR1, limiting axon regeneration have been identified, they provide an incomplete explanation for poor adult mammalian CNS regeneration. We completed a genome-wide shRNA screen for endogenous genes limiting mammalian CNS axon repair. The validity of this method was demonstrated by the identification of INPP5F as a gene limiting neural repair in a pilot screen of phosphatases. One cellular pathway is bioinformatically the most enriched gene set in the mammalian screen, and also regulates regeneration in nematodes. The relevance of this pathway will be tested in preclinical models of traumatic SCI. Both gene deletion strains and pharmacological inhibition will be studied to provide a validated pathway for future therapeutic development. The findings will have high relevance for the development of novel therapeutics for SCI.