Combined stem cell transplantation and targeted microstimulation to direct the fo

描述（由申请人提供）：本研究的目标是开发和测试一种指导中枢神经系统损伤或退化后修复和再生的方法。我们提出，通过创造再生环境和指导神经元之间的内在可塑性，我们可以实现神经修复的一个新的里程碑。如果成功，这种方法可以用于治疗中枢神经系统损伤的患者，如创伤性脑损伤、中风或脊髓损伤，以减轻神经系统疾病对个人和社会的负担。我们的研究采用靶向电微刺激和干细胞治疗的新组合来指导绕过损伤形成适当和功能性的连接。我们将在不完全性颈脊髓损伤的啮齿动物模型中测试我们的方法，该模型代表了整个中枢神经系统的损伤。众所周知，在神经系统发育过程中，干细胞产生未成熟的星形胶质细胞，为支持轴突引导和突触可塑性创造环境。在这里，我们假设神经可塑性和受损神经元的修复可以通过重建损伤部位周围星形胶质细胞的发育表型来促进。在这类方法中，我们将从自体成体干细胞中获得未成熟的星形胶质细胞，并将其移植到脊髓病变附近，以创造一个支持可塑性和神经修复的环境。我们认为，仅提供环境支持的效果有限，因为它没有解决神经元生长的内在驱动。在完整和受损的神经系统中，同步和适当的神经活动也需要指导功能性突触连接的形成。在这里，我们将使用一种神经假体装置向脊髓损伤下方的目标部位提供微刺激，这与运动皮层的功能相关活动同步。定向微刺激将通过Hebbian可塑性机制加强适当和功能性的连接。我们的方法不是试图在脊髓中进行长束再生，而是通过绕过病变的备用通路促进间接连接的形成。恢复的程度将通过行为任务、电生理和组织学方法来测量。这将决定同步、靶向微刺激引导移植干细胞在中枢神经系统受损后形成适当和功能性连接的能力。我们认为，微刺激将与移植环境合作，对局部可塑性产生倍增效应。

DESCRIPTION (provided by applicant): The goal of this research is to develop and test a method to guide repair and regeneration of the central nervous system following injury or degeneration. We propose that by creating both a regenerative environment as well as directing intrinsic plasticity among neurons, we can achieve a new milestone in neural repair. If successful, this approach could be used to treat patients suffering from central nervous system damage such as traumatic brain injury, stroke, or spinal cord injury in order to reduce the burden of neurological disease on individuals and society. Our studies employ a novel combination of targeted electrical microstimulation and stem cell therapies to guide the formation of appropriate and functional connections bypassing an injury. We will test our approach in a rodent model of incomplete cervical spinal cord injury that is representative of insults throughout the central nervous system. It is known that during development of the nervous system, stem cells produce immature astrocytes that create an environment to support axon guidance and synaptic plasticity. Here, we hypothesize that neural plasticity and the repair of damaged neurons can be facilitated by re-creating the developmental phenotype of astrocytes surrounding an injury site. In a first of its kind approach, we will derive immature astrocytes from autologous adult stem cells and transplant them near a spinal cord lesion to create a supportive environment for plasticity and neural repair. We propose that providing environmental support alone has had limited success because it does not address the intrinsic drive of neurons to grow. Synchronous and appropriate neural activity is also needed to direct the formation of functional synaptic connections in the intact and injured nervous system. Here we will use a neuroprosthetic device to deliver microstimulation to targeted sites within the spinal cord below the injury that is synchronized with functionally related activity in the motor cortex. Targeted microstimulation will strengthen appropriate and functional connections via mechanisms of Hebbian plasticity. Rather than attempt long-tract regeneration in the spinal cord, our approach aims to promote the formation of indirect connections via spared pathways bypassing the lesion. The extent of recovery will be measured using behavioral tasks, and electrophysiological and histological methods. This will determine the ability of synchronous, targeted microstimulation to guide implanted stem cells in the formation of appropriate and functional connections following damage to the central nervous system. We contend that microstimulation will collaborate with the transplant environment to produce a multiplicative effect on local plasticity. PUBLIC HEALTH RELEVANCE: This research aims to develop a treatment for damage to the brain or spinal cord as occurs, for example, following traumatic brain injury, stroke, or spinal cord injury. Targeted electrical microstimulation will be applied across the injury in order to guide implanted stem cells to make appropriate connections and restore function following injury.