Genome-Wide Discovery and Translational Research for Neural Repair

摘要 脊髓损伤(SCI)后发生破坏性和持续性的神经功能障碍，尽管 所有的神经元。致残的主要原因是轴突横断导致的网络断开。恢复 一些活动就足以让患者在轮椅转移中获得一定程度的独立性， 大便和膀胱管理，以及运动。今天，30万人还没有得到批准的药物治疗 给美国120万名患有脊髓损伤的人。 成年哺乳动物的中枢神经系统，与哺乳动物的周围神经系统或神经系统相比 轴突再生能力极其有限。我们的轴突生长研究 包括Nogo和Nogo受体(NgR1)的发现。我们展示了它们在防止轴突形成中的作用。 萌发、再生和受伤后的恢复。我们已经证明了NgR1(310)-Fc是有效的 从脊髓损伤中恢复，即使在损伤几个月后开始治疗。它是为人类SCI而开发的 现在开始审判。 虽然已经确定了特定的因素，如NgR1，限制轴突再生，但它们提供了一种 对成年哺乳动物中枢神经系统再生能力差的解释不完全。我们完成了全基因组的shRNA 筛选限制哺乳动物中枢神经系统轴突修复的内源性基因。该方法的有效性是 在磷酸酶的初步筛选中，INPP5F被确认为一种限制神经修复的基因。 一种细胞途径是生物信息学上哺乳动物筛选中最丰富的基因集，而且 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。将对基因缺失菌株和药理抑制进行研究，以提供经过验证的 未来治疗发展的途径。这些发现将对小说的发展具有很高的现实意义 脊髓损伤治疗学。

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.