Tailoring Neural Transplants for Cervical Spinal Cord Repair

项目总结/摘要 干细胞技术为目前缺乏的一些最具破坏性的医疗条件提供了新的希望 治疗。然而，为了充分利用干细胞的治疗潜力，有必要了解 如何引导它们分化为适当的细胞表型，了解它们在体外如何变化， 操作，以及外部环境如何影响移植到受伤或患病后的保真度 主机网络。这些知识差距是我长期培训计划的基石。我的研究目标 是成为一名独立的科学家，从事与学术相关的研究。为了做到这一点，我将建立在我的 从本科研究的技术体外技能，现在使用的临床前脊髓损伤模型作为一个 这是我关于移植工程细胞的治疗潜力的假设的试验平台。一半以上 所有脊髓损伤中的1/4发生在颈部，导致严重的呼吸功能障碍和并发症。这些 缺陷主要是由于下行球脊髓呼吸通路的中断和脊髓损伤， 呼吸运动回路虽然目前的疗法旨在增强备用网络的可塑性，但它们 未能治疗缺陷的根本原因：神经丧失。神经修复的一个有希望的策略是使用 细胞移植，但很少有人知道他们的表型，发展和连接到主机 移植后的网络重要的是，关于这些细胞如何随着时间的推移而变化， 体外操作（例如，添加生长因子，冷冻保存如何改变表型潜力， 等）。神经前体细胞（NPC）已被用于修复受损的中枢神经系统数十年。 然而，这些供体细胞群是高度异质的，尚未得到很好的表征， 制备这些用于移植的细胞可以进一步改变它们的异质性。当前的主要目标 研究旨在解决这一问题，并通过富集特定的脊髓亚群来增强其治疗潜力。 中间神经元已知有助于有益的可塑性和修复。目前的建议将测试治疗 富含运动前V0脊髓中间神经元的供体NPC的精制群体促进 SCI后的解剖（目标1）和功能（目标2）改善。

PROJECT SUMMARY/ABSTRACT Stem cell technologies offer new promise for some of the most devastating medical conditions that currently lack treatments. To harness the full therapeutic potential of stem cells, however, it will be necessary to understand how to direct their differentiation to appropriate cell phenotypes, understand how they may change with in vitro manipulation, and how the external milieu may influence their fidelity after transplantation into injured or diseased host networks. These gaps in knowledge are the cornerstones of my long-term training plan. My research goal is to become an independent scientist pursuing translationally relevant research. To do so, I will build upon my technical in vitro skills from undergraduate research, and now use a model of pre-clinical spinal cord injury as a testbed for my hypotheses regarding the therapeutic potential of transplanted engineered cells. More than half of all spinal cord injuries occur at the cervical level resulting in major respiratory deficits and complications. These deficits are largely due to the disruption of descending bulbospinal respiratory pathways and damage to spinal respiratory motor circuits. While current therapies are aimed at enhancing the plasticity of spared networks, they fail to treat the underlying cause of deficits: neural loss. One promising strategy for neural repair is the use of cellular transplants, yet very little is known about their phenotype, development, and connectivity to host networks after transplantation. Importantly, even less is known about how these cells change with each manipulation in vitro (e.g., addition of growth factors, how cryopreservation may change the phenotypic potential, etc.). Neural precursor cells (NPCs) have been used for decades to repair the injured central nervous system. However, these donor cell populations are highly heterogeneous, have not been well characterized and preparation of these cells for transplantation may further alter their heterogeneity. A primary goal of the present study is to address this issue and enhance their therapeutic potential by enriching for specific subsets of spinal interneurons known to contribute to beneficial plasticity and repair. The current proposal will test the therapeutic potential of refined populations of donor NPCs, enriched with pre-motor V0 spinal interneurons, to promote anatomical (Aim 1) and functional (Aim 2) improvement post-SCI.