Training Novel Host-Graft Interfaces to Enhance Spinal Cord Repair

训练新型宿主-移植物界面以增强脊髓修复

• 批准号: 8111597
• 负责人: DAVID D FULLER
• 金额: $ 17.75万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111597
• 关键词: Adult; Animals; Breathing; Cell Transplantation; Cell Transplants; Cells; Cervical; Cervical spinal cord injury; Communication; Contusions; Coupling; Data; Effectiveness; Exhibits; Exposure to; Human; Hypoxia; Injection of therapeutic agent; Injury; Interneurons; Intervention; Lesion; Measurement; Mediating; Methods; Microelectrodes; Modeling; Monitor; Motor; Motor Neurons; Motor output; Neurobiology; Neuronal Plasticity; Neurons; Output; Pattern; Phrenic Motor System; Physiological; Protocols documentation; Rattus; Recovery; Rehabilitation therapy; Replacement Therapy; Source; Spinal; Spinal Cord; Spinal Cord Lesions; Spinal Cord Plasticity; Spinal Injuries; Spinal cord injury; Stem cells; Suid Herpesvirus 1; Suspension substance; Suspensions; Synapses; Testing; Tissue Grafts; Tissues; Training; Transplantation; Work; Wound Healing; awake; base; clinically relevant; experience; fetal; functional outcomes; gray matter; improved; injured; innovation; nerve stem cell; neuronal replacement; neurophysiology; neurotransmitter agonist; neurotransmitter antagonist; novel; programs; relating to nervous system; research study; respiratory; spinal cord repair; tool

DESCRIPTION (provided by applicant): Neuronal replacement shows promise for enhancing recovery after spinal cord injury (SCI), and is considered a major objective for stem cell-mediated spinal cord repair. Achieving effective host-graft neuronal communication, however, represents a major challenge for neuronal replacement which has not been investigated. The overall hypothesis of this proposal is that presenting newly established host-graft neuronal networks with physiologically-patterned activities will enhance functional connectivity. Based on our extensive experience with SCI modeling and both respiratory and computational neurobiology, we are proposing to test this hypothesis by transplanting rat fetal spinal cord (FSC) tissue grafts - a source of neuronal progenitors - into clinically-relevant, high cervical (C3) contusion injuries in adult rats. Preliminary transneuronal neuroanatomical tracing data show synaptic connectivity between FSC donor cells and host phrenic motoneurons and cervical interneurons. In addition, FSC grafts receive extensive serotonergic inputs from the host, and some graft neurons exhibit hypoxia-sensitive discharge patterns including apparent inspiratory- related bursting. A prerequisite anatomical-functional framework is thus in place to test our central hypothesis via the following specific aims using FSC grafts placed into C3 contusion injuries in adult rats: Aim 1) to test the hypothesis that FSC-derived neurons will become anatomically and physiologically integrated with host gray matter, and Aim 2) to test the hypothesis that "training" via intermittent hypoxia (IH) stimulation will enhance the anatomical and physiological integration of FSC-derived neurons. To test these hypotheses, we will use a multi-disciplinary approach including neuroanatomical studies of connectivity between the graft and host spinal cord, measurement of breathing in awake rats, and neurophysiological studies of the graft. An innovative technical feature of our proposal is that this will be the first use of microelectrode arrays to monitor graft- associated neural ensembles in the spinal cord. A FSC grafting method will be used because such grafts develop into myelinated tissue containing a large contingent of cells resembling intermediate gray matter interneurons. A unique rehabilitative paradigm - daily exposure to mild, intermittent hypoxia (IH) - will be used because it leads to spinal cord plasticity associated with persistent increases in respiratory output in spinal injured animals. Equally important, IH provides a tool to introduce or increase appropriately patterned bursting around, and possibly within, the graft. This proposal brings together unique expertise in respiratory neurophysiology, computational neurobiology, neural transplantation, and SCI in an effort to facilitate transformative advances in the understanding and treatment of SCI. PUBLIC HEALTH RELEVANCE: Respiratory compromise is a significant problem after cervical spinal cord injury. A strategy that may enhance motor recovery after spinal injury is "neural replacement" therapy in which cells are transplanted into the spinal cord lesion. In these experiments, we will examine if a novel rehabilitation paradigm can enhance the effectiveness of a neural transplant following spinal cord injury.

描述（由申请人提供）：神经元替代显示出增强脊髓损伤（SCI）后恢复的希望，被认为是干细胞介导的脊髓修复的主要目标。然而，实现有效的宿主-移植物神经元通信是神经元替代的主要挑战，尚未进行研究。该建议的总体假设是，呈现新建立的宿主-移植物神经网络的生理模式活动将增强功能连接。基于我们在脊髓损伤建模以及呼吸和计算神经生物学方面的丰富经验，我们建议通过将大鼠胎儿脊髓（FSC）组织移植物（神经元祖细胞的来源）移植到临床相关的成年大鼠高颈椎（C3）挫伤中来验证这一假设。初步的跨神经元神经解剖示踪数据显示FSC供体细胞与宿主膈运动神经元和颈间神经元之间存在突触连通性。此外，FSC移植物接受来自宿主的大量血清素输入，一些移植物神经元表现出缺氧敏感的放电模式，包括明显的吸气相关的破裂。因此，通过将FSC移植物植入成年大鼠的C3挫伤中，一个先决的解剖-功能框架已经到位，可以通过以下具体目标来验证我们的中心假设：目的1)验证fsc源性神经元与宿主灰质在解剖和生理上整合的假设；目的2)验证间歇性缺氧（IH）刺激的“训练”将增强fsc源性神经元在解剖和生理上整合的假设。为了验证这些假设，我们将采用多学科方法，包括移植物和宿主脊髓之间连通性的神经解剖学研究，清醒大鼠呼吸测量以及移植物的神经生理学研究。我们的提议的一个创新的技术特点是，这将是第一次使用微电极阵列来监测脊髓中移植物相关的神经系统。将使用FSC移植方法，因为这种移植物发育成含有大量类似中间灰质中间神经元的细胞的髓鞘组织。将采用一种独特的康复模式——每天暴露于轻度间歇性缺氧（IH），因为它会导致脊髓可塑性，并与脊髓损伤动物的呼吸输出量持续增加有关。同样重要的是，IH提供了一种工具，可以在移植物周围或可能在移植物内部引入或增加适当的模式破裂。该提案汇集了呼吸神经生理学，计算神经生物学，神经移植和SCI方面的独特专业知识，以促进对SCI的理解和治疗的变革性进展。