Imaging of Brain Remodeling and Functional Recovery

该项目的目标是开发磁共振成像（MRI）作为一种工具， 有创评估和监测中风患者的恢复情况。我们的研究在目前的资金 研究表明，某些药物可以促进实验性中风后的功能恢复， 基于组织学和功能评估的动物。一个主要的候选人， 药物是西地那非，一种磷酸二酯酶5型抑制剂，已广泛用于人类 增加环磷酸鸟苷（cGMP）。我们的数据显示西地那非显著 改善中风后年轻和老年动物的功能恢复。因此，我们将采用 西地那非在拟议的研究。我们还生成了初步的成像数据， 表明某些MRI方法可能对中风后组织重构（血管 和神经元）被认为影响最终结果的事件。报告中提出的研究 当前的应用通过组合和应用这些新颖的成像来扩展该主题， 组织学和恢复性治疗策略，以评估卒中后血管（目标1）和 神经元（目的2）重塑在年轻和老年动物与和没有恢复 疗法MRI将用于识别、表征和定义组织重塑事件， 有助于改善卒中后的远期功能结局。这些MRI评估 将与确定的组织重塑的相应测量进行比较和关联 从三维激光扫描共聚焦显微镜和免疫组织化学。最后，目标3将研究 神经元和血管的各种MRI与组织学指标的关系 重塑，并将这些数据与功能结果相关联， 行为测试拟议的研究是新颖和创新的，使我们的研究远离 中风治疗的急性诊断和神经保护治疗方法， 促进脑组织重塑的晚期恢复性治疗的相对未开发的领域 最终改善功能结局的事件。如果成功，这些研究预计将 产生关于中风后脑组织重塑的突破性信息， 用于监测中风恢复，并可能导致治疗方案的优化， 使所有中风患者受益。

The objective of this project is to develop magnetic resonance imaging (MRI) as a tool to non- invasively evaluate and monitor recovery in stroke patients. Our studies during the current funding period indicate that certain agents can enhance functional recovery after stroke in experimental animals based on histological and functional assessments. A prime candidate among restorative agents is sildenafil, a phosphodiesterase type-5 inhibitor, which has been widely used in humans to increase cyclic guanosine monophosphate (cGMP). Our data show that sildenafil significantly improves functional recovery in both young and aged animals after stroke. Hence, we will employ sildenafil in the proposed studies. We have also generated preliminary imaging data, which indicate that certain MRI methods may be sensitive to post-stroke tissue remodeling (vascular and neuronal) events that are thought to influence eventual outcome. The studies proposed in the current application expand on this theme by combining and applying these novel imaging, histological and restorative treatment strategies to assess post-stroke vascular (Aim 1) and neuronal (Aim 2) remodeling in both young and aged animals with and without restorative therapy. MRI will be used to identify, characterize and define tissue-remodeling events that contribute to improvement of late-term functional outcome after stroke. These MRI assessments will be compared and correlated to corresponding measures of tissue remodeling determined from 3D laser scanning confocal microscopy and immunohistochemistry. Finally, Aim 3 will study the relationship between the various MRI and histological indices of neuronal and vascular remodeling and will relate these data to functional outcome as measured by a battery of behavioral tests. The proposed studies are novel and innovative, moving our research away from acute diagnostics and neuroprotective therapeutic approaches for stroke treatment and toward a relatively unexplored area of late-term restorative therapy that promotes brain tissue remodeling events that ultimately improve functional outcome. If successful, these studies are expected to generate ground breaking information about post-stroke brain tissue remodeling that will be useful for monitoring stroke recovery and may lead to optimization of treatment protocols that would benefit all stroke patients.