Treatment of Neural Injury with MSCs

描述(由申请人提供)： 该计划项目应用的基本假设是，通过静脉途径将骨髓基质细胞(MSCs)输送到脑内可用于改善神经损伤后的功能结局，特别是中风和创伤性脑损伤。 提出了三个补充项目和两个支持核心：项目1/骨髓间充质干细胞治疗中风；项目2/骨髓间充质干细胞治疗创伤性脑损伤；项目3/骨髓间充质干细胞与组织的相互作用分析。核心A为计划项目提供行政和生物统计学支持，核心B提供中风和创伤后功能和行为的结果指标、对损伤和治疗的细胞和分子反应的指标，以及用于治疗的细胞的准备。项目1和2将确定将MSC疗法应用于中风(年轻和老年动物，男性，女性)和创伤性脑损伤(年轻男性)的大鼠和小鼠实验模型的最佳方法，并将安全性作为首要考虑因素。需要检验的假设是，大脑中的MSCs会激发营养因子的产生，这些营养因子会改变受损的大脑，从而促进功能受益。静脉注射给动物的骨髓基质细胞可以找到途径到达缺血或受损的脑组织，并促进功能改善。因此，在临床相关的静脉给药条件下，项目1(中风)和项目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后大脑的结构和形态变化，并阐明受伤的大脑对MSC治疗的反应。项目3将利用抗体、转基因小鼠和一系列新技术来研究骨髓间充质干细胞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，即血管内皮生长因子、碱性成纤维细胞生长因子和脑源性神经营养因子被确定为(在项目I和2中)作为MSC治疗益处的关键介质。在项目3中，这些因子在接受MSC治疗的小鼠身上进行操作，以确定它们在MSC治疗中风和创伤中的作用，重点是这些因子如何通过MSC治疗在受损组织中诱导，促进可塑性和神经保护。本计划项目申请的长期目标是将我们在使用MSCs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.