Tailoring Neural Transplants for Cervical Spinal Cord Repair

定制神经移植用于颈脊髓修复

• 批准号: 10537226
• 负责人: Tara Fortino
• 金额: $ 4.68万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537226
• 关键词: Address; American; Anatomy; Animals; Breathing; Caring; Cell Line; Cell Therapy; Cell Transplantation; Cells; Cervical; Cervical spinal cord injury; Cervical spinal cord structure; Climacteric; Clinical; Clozapine; Contusions; Cryopreservation; Data; Development; Disease; Engineering; Future; Glial Fibrillary Acidic Protein; Goals; Growth Factor; Heterogeneity; Immunohistochemistry; Impairment; In Vitro; Injury; Interneurons; Knowledge; Lesion; Life; Measures; Mediating; Medical; Motor; Motor Neurons; Mus; Nature; Neck; Neuroglia; Neuronal Plasticity; Neurons; Oxides; Pathway interactions; Phenotype; Physical Stimulation; Physical therapy; Play; Population; Pre-Clinical Model; Puromycin; Recording of previous events; Recovery; Recovery of Function; Rehabilitation therapy; Reporter; Research; Resistance; Respiratory Diaphragm; Role; Scientist; Sensory; Source; Specificity; Spinal; Spinal cord injury; Synapses; Synaptophysin; Telemetry; Therapeutic; Tissues; Training; Transplantation; Treatment Efficacy; Work; awake; cell preparation; cell type; cellular engineering; central nervous system injury; cholinergic; cholinergic neuron; designer receptors exclusively activated by designer drugs; disability; experimental study; improved; improved outcome; injured; injury and repair; injury recovery; innovation; insight; mad itch virus; motor recovery; nerve injury; nerve stem cell; neural repair; post-transplant; pre-clinical; precursor cell; presynaptic; programs; promoter; receptor; relating to nervous system; repaired; reparative capacity; respiratory; skills; spinal cord repair; stem cell technology; stem cells; synaptogenesis; therapeutic evaluation; undergraduate research

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.

项目概要/摘要 干细胞技术为目前缺乏的一些最具破坏性的医疗状况提供了新的希望 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，了解它们在体外可能如何变化 操纵，以及移植到受伤或患病后外部环境如何影响它们的保真度 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 是成为一名独立科学家，从事转化相关的研究。为此，我将在我的基础上 来自本科生研究的体外技术技能，现在使用临床前脊髓损伤模型作为 我关于移植工程细胞治疗潜力的假设的测试平台。超过一半 所有脊髓损伤中的一半发生在颈部，导致严重的呼吸缺陷和并发症。这些 缺陷主要是由于球脊髓下降呼吸通路的破坏和脊髓损伤 呼吸运动回路。虽然当前的疗法旨在增强幸存网络的可塑性，但它们 未能治疗缺陷的根本原因：神经损失。一种有前景的神经修复策略是使用 细胞移植，但对其表型、发育和与宿主的连接性知之甚少 移植后的网络。重要的是，我们对这些细胞如何随时间变化而知之甚少。 体外操作（例如，添加生长因子、冷冻保存如何改变表型潜力、 ETC。）。几十年来，神经前体细胞（NPC）一直被用来修复受损的中枢神经系统。 然而，这些供体细胞群具有高度异质性，尚未得到很好的表征和鉴定 这些用于移植的细胞的制备可能会进一步改变它们的异质性。当前的首要目标 研究的目的是解决这个问题，并通过丰富脊柱的特定子集来增强其治疗潜力 已知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效果 富含运动前 V0 脊髓中间神经元的精炼供体 NPC 群体的潜力，以促进 SCI 后解剖学（目标 1）和功能（目标 2）的改善。