Treatment of Neural Injury with MSCs

描述（由申请人提供）： 该计划项目申请的基本假设是，通过静脉途径递送至大脑的骨髓基质细胞（MSC）可用于改善神经损伤后的功能结果，特别是中风和创伤性脑损伤。 提出了三个互补项目和两个支持核心：项目1用MSC治疗中风;项目2/用MSC治疗创伤性脑损伤;项目3/MSC与组织相互作用的分析。核心A为计划项目提供管理和生物统计支持，核心B提供卒中和创伤后功能和行为的结局指标，对损伤和治疗的细胞和分子反应指标，以及用于治疗的细胞制备。项目1和2将确定将MSC治疗分别应用于中风大鼠和小鼠实验模型（年轻和老年动物，雄性、雌性）和创伤性脑损伤（年轻男性）的最佳方法，安全性是首要考虑因素。待检验的假设是，脑中的MSC引起营养因子的产生，所述营养因子改变受损的脑以促进功能益处。静脉内给予动物的骨髓基质细胞找到它们到达缺血或受损脑组织的途径并促进功能改善。因此，在静脉给药的临床相关条件下，项目1（中风）和2（创伤性脑损伤）将优化和定义治疗干预的边界，测量特定的神经营养因子以及治疗脑中的结构和形态变化，并阐明受损脑如何对MSC治疗作出反应。项目3将采用抗体、转基因小鼠和一系列新技术来研究MSC治疗中风和创伤提供功能改善的机制。一组特定的神经营养因子，即VEGF、bFGF和BDNF被鉴定（在项目I和2中）为MSC治疗益处的关键介质。在项目3中，在MSC治疗的小鼠中操纵这些因子，以确定它们在MSC治疗中风和创伤中的作用，重点是MSC治疗如何在损伤组织中诱导这些因子，促进可塑性和神经保护。该计划项目申请的长期目标是将我们发现的用MSC治疗实验性中风和创伤性脑损伤后的治疗益处转化为患者。

DESCRIPTION (provided by applicant): The underlying hypothesis of this Program Project application is that bone marrow stromal cells (MSCs) delivered to brain via an intravenous route can be employed to improve functional outcome after neural injury, specifically, stroke and traumatic brain injury. Three complementary projects and two supporting cores are proposed: Project 1 Treatment of Stroke with MSCs; Project 2/Treatment of Traumatic Brain Injury with MSCs; Project 3/Analysis of MSC Interaction with Tissue. Core A provides the administrative and biostatistical support for the Program Project, and Core B provides the outcome measures of function and behavior after stroke and trauma, measures of cellular and molecular responses to injury and treatment, and the preparation of cells to be employed for treatment. Projects 1 and 2, will determine the optimal means of applying MSC therapy to experimental models in the rat and the mouse of stroke (young and old animals, male, female) and traumatic brain injury (young male), respectively, with safety as an overriding consideration. The hypothesis to be tested is that MSCs in brain evoke the production of trophic factors that alter injured brain to promote functional benefit. Marrow stromal ceils administered to animals intravenously find their way to ischemic or damaged cerebral tissue and foster functional improvement. Thus, under the clinically relevant conditions of intravenous administration, Projects 1 (stroke) and 2 (traumatic brain injury) will optimize and define the boundaries of therapeutic intervention, measure specific neurotrophic factors and structural and morphological changes in treated brain and clarify how the injured brain responds to MSC treatment. Project 3, will employ antibodies, and genetically modified mice and an array of novel technologies to investigate the mechanisms by which treatment of stroke and trauma with MSCs provides functional improvement. A specific set of neurotrophic factors i.e. VEGF, bFGF and BDNF are identified (in Projects I and 2) as key mediators of MSC therapeutic benefit. In Project 3, these factors are manipulated in the MSC treated mouse to determine their roles in MSC therapy of stroke and trauma, with an emphasis on how these factors induced in injured tissue by MSC treatment, promote plasticity and neuroprotection. The long-term goal of this Program Project application is to translate our finding of therapeutic benefit after treatment of experimental stroke and traumatic brain injury with MSCs to the patient.