Tailoring Neural Transplants for Cervical Spinal Cord Repair

项目摘要/摘要 干细胞技术为目前缺乏的一些最具破坏性的医疗疾病提供了新的希望 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合适的细胞表型，了解它们在体外可能会发生什么变化 操作，以及外部环境如何影响他们在移植到受伤或患病的体内后的保真度 主机网络。这些知识上的差距是我长期培训计划的基石。我的研究目标 成为一名从事翻译相关研究的独立科学家。要做到这一点，我将在我的 来自本科研究的体外技术，现在使用临床前脊髓损伤的模型作为 为我关于移植的工程细胞的治疗潜力的假设提供了试验台。过半 所有的脊髓损伤都发生在颈椎水平，导致严重的呼吸障碍和并发症。这些 缺陷很大程度上是由于球脊髓下行呼吸道的中断和脊髓损伤。 呼吸马达电路。虽然目前的治疗方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。一种有希望的神经修复策略是使用 细胞移植，但对其表型、发育和与宿主的连通性知之甚少 移植后的网络。重要的是，人们对这些细胞如何变化知之甚少。 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)。神经前体细胞用于修复受损的中枢神经系统已有数十年的历史。 然而，这些供体细胞群体是高度异质性的，尚未得到很好的表征和 为移植准备这些细胞可能会进一步改变它们的异质性。当前的首要目标 研究旨在解决这一问题，并通过丰富特定的脊椎亚群来增强其治疗潜力 已知的中间神经元有助于有益的可塑性和修复。目前的提案将测试治疗方法 富含运动前V0脊髓中间神经元的精制供体神经前体细胞群体促进 脊髓损伤后解剖(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.