Imaging Cell Based Treatment of Traumatic Brain Injury

描述(申请人提供)：我们的建议有两个主要的创新方面：1)开发磁共振成像(MRI)作为监测和预测创伤性脑损伤(TBI)后功能恢复的手段；以及2)早期(即在损伤后24小时内)应用骨髓基质细胞(MSCs)治疗脑损伤，作为一种神经保护和神经恢复疗法。骨髓间充质干细胞用于脑外伤的神经修复治疗，在促进神经元重塑和改善功能恢复方面显示出良好的前景。然而，我们和其他人还没有研究在损伤后24小时内早期使用MSCs治疗的益处。此外，迫切需要无创地监测大脑重塑和功能恢复，并将这些方法从实验研究转化为临床研究。我们认为，MRI可以灵敏地监测脑损伤后正在进行的反映神经功能的脑组织结构重构，因此，MRI可以用于评估脑损伤患者的康复情况，并最终应用于脑损伤患者。在这项研究中，我们将发展和实施MR方法来研究早期和晚期MSC治疗对脑创伤后MSCs迁移、分布和损伤体积的影响(目标1)、轴突重组(目标2)以及脑重塑与功能恢复(目标3)的关系。脑重塑的MRI测量将使用三维激光扫描共聚焦显微镜和免疫组织化学来验证。神经结果将通过一系列行为测试进行评估。通过这些新的方法，我们期望MRI方法测量MSCs的分布和浓度以及轴突重组是监测脑损伤恢复性治疗后恢复情况的有效新工具。这些方法应该导致治疗方案的优化和改善对脑外伤恢复的管理。 公共卫生相关性：利用脑神经突起重组和骨髓基质细胞(MSC)分布的MR测量来预测创伤性脑损伤(TBI)后脑功能恢复的早期MSC治疗的研究，可能为改善TBI的恢复提供新的患者治疗方法。这些研究有可能极大地提高颅脑损伤的神经学预后，并无创地监测导致功能恢复的相关轴突重组。

DESCRIPTION (provided by applicant): There are two major innovative aspects to our proposal: 1) To develop magnetic resonance imaging (MRI) as a means to monitor and predict functional recovery after traumatic brain injury (TBI); and 2) To treat TBI with bone marrow stromal cells (MSCs) early, i.e. within 24 hours of injury, as a neuroprotective and neurorestorative therapy. Neurorestorative treatment of TBI using MSCs has demonstrated promise in promoting neuronal remodeling, and improvement of functional recovery. However, we and others have not studied the beneficial effects of early, within 24 hours of injury, treatment with MSCs. Also, there is a compelling need to noninvasively monitor brain remodeling and functional recovery and to translate these methodologies from experimental studies to the clinic. We propose that MRI can sensitively monitor ongoing structural remodeling of brain tissue after TBI that reflects neurological function, and therefore, MRI can be employed to assess recovery and ultimately be applied to the TBI patient. In this proposal, we will develop and implement MR methodologies to investigate the effects of early and late MSC treatment on the migration and distribution of MSCs and lesion volume after TBI (Aim 1), neurite reorganization (Aim 2), and the relationship between brain remodeling and functional recovery (Aim 3) in the experimental animal subjected to TBI. MRI measurements of brain remodeling will be verified using three dimensional laser scanning confocal microscopy and immuno-histochemistry. Neurological outcome will be assessed using a battery of behavioral tests. With these novel approaches, we expect that MRI methodologies for measurement of distribution and concentration of MSCs and neurite reorganization are valid new tools for monitoring the recovery from TBI after restorative therapy. These methods should lead to optimization of treatment protocols and improved management of recovery from TBI. PUBLIC HEALTH RELEVANCE: The investigation of early MSC therapy of TBI utilizing MR-measures of brain neurite reorganization and bone marrow stromal cell (MSC) distribution for predicting brain functional recovery after traumatic brain injury (TBI) and could promise new patient therapies aimed at improving TBI recovery. These studies have the potential to greatly enhance neurological outcomes from TBI and to noninvasively monitor the associated neurite reorganization leading to the recovery of functions.