Embryonic Stem Cell Therapy after Cervical Contusion SCI in NHPs

这项新的应用代表了加州灵长类动物脊髓研究的延续 人胚胎干细胞（hESC）衍生神经干细胞的联盟计划 移植;我们的首要目标是了解脊髓的两种基本机制 组织和功能，并利用这些和其他进展， 开发人类转化促再生疗法。我们已经取得了可观的 过去五年取得的进展，现在提出新的具体目标，将直接影响到 人类神经干细胞（NSC）对人类SCI有益的潜力。 目的1：研究移植相关功能改善的机制：移植 抑制性DREADD沉默。这方面的工作将确定 在非人灵长类动物中观察到的脊髓神经干细胞移植后的恢复与 移植激活宿主的神经回路这些知识对于人工翻译来说非常重要。 目的2：确定4-AP是否改善术后的解剖和功能结局 神经干细胞移植有大量文献支持神经干细胞移植的潜在有益作用。 4AP在SCI中，并且4AP被批准用于人类作为多种疾病中的传导增强药物。 硬化症这一目标将确定神经干细胞移植物加4AP治疗是否 改善解剖和功能结果。 目的3：确定PTEN/SOCS3抑制是否改善宿主皮质脊髓 再生和功能结果。啮齿动物研究表明， 神经干细胞移植物通过宿主-移植物-宿主电生理通路的形成来介导 在SCI的站点之间中继。这些中继需要宿主轴突再生到移植物中。在人类中， 皮质脊髓轴突对于随意运动是必需的。这一目标将决定 PTEN/SOCS3失活将增强皮质脊髓轴突再生， 灵长类动物的功能结果。

This new application represents a continuation of the California Primate Spinal Cord Research Consortium project on human embryonic stem cell (hESC) derived neural stem cell transplantation; our overarching goal is to understand both basic mechanisms of spinal cord organization and function in non-human primates, and to leverage these and other advances in developing translational human pro-regenerative therapies. We have made considerable progress in the last 5 years and now propose new specific aims that will directly bear on the potential of human neural stem cells (NSCs) to benefit human SCI. Aim 1: Examine Mechanisms Underlying Graft-Related Functional Improvement: Graft Silencing with Inhibitory DREADDs. Work in this aim will establish whether functional recovery observed in non-human primates after grafts of spinalized neural stem cells is related to graft activation of host neural circuits. This knowledge will be important for human translation. Aim 2: Determine Whether 4-AP Improves Anatomical and Functional Outcomes After Neural Stem Cell Grafts There is a vast literature supporting potentially beneficial effects of 4AP in SCI, and 4AP is approved for human use as a conduction-enhancing drug in multiple sclerosis. This aim will determine whether treatment with neural stem cell grafts plus 4AP improves anatomical and functional outcomes. Aim 3: Determine Whether PTEN/SOCS3 Inhibition Improves Host Corticospinal Regeneration and Functional Outcomes. Rodent studies indicate that functional benefits of neural stem cell grafts are mediated by formation of host-to-graft-to-host electrophysiological relays across sites of SCI. These relays require host axon regeneration into grafts. In humans, corticospinal axons are essential for voluntary movement. This aim will determine whether inactivation of PTEN/SOCS3 will enhance corticospinal axon regeneration and improve functional outcomes in primates.