Cellular and molecular mechanisms of brain repair by glial scar formation following stroke

项目描述 该项目致力于中风患者的康复和中风后痴呆症的发展，这是一个亚组， 这是一种血管性痴呆，影响了大约三分之一的中风患者。中风后， 血脑屏障（BBB）在病变区域被破坏。作为细胞修复反应的一部分， 星形胶质细胞通过一种未知的机制结合在一起，形成一个物理屏障，封闭受损区域， 保护幸存的神经元星形胶质细胞增生和胶质瘢痕的形成是神经胶质细胞增生的重要组成部分。 对中风的治疗反应然而，目前还没有关于胶质瘢痕失败的可能性的研究， 以完美地封闭损伤区域，我们最近证明，这也是一个慢性炎症部位， 反应，导致中风后痴呆患者的认知能力下降。这种局限性 部分原因是缺乏有效的中风后迟发性认知功能障碍的动物模型。 然而，我们最近开发了一种创新的迟发性认知功能障碍小鼠模型， 中风后痴呆的典型特征。使用这个模型，我们现在有大量的证据表明， 神经胶质瘢痕未能分离病变内的慢性渗漏血管，以及慢性渗漏血管， 在损伤中发生的炎症反应是中风后痴呆的原因之一。因此， 这个项目是为了第一次精确地确定胶质瘢痕如何（以及如何有效地）密封该区域。 中风后的损伤，通过确定涉及的细胞和分子机制，然后操纵 这些机制来增强神经胶质瘢痕的修复。这些目标将通过使用我们的新鼠标来实现 脑卒中后迟发性认知功能障碍模型结合共聚焦和电子显微镜， 免疫组织化学、生物化学测定、流式细胞术、多重免疫测定和行为研究， 成年和老年野生型和转基因小鼠。在这些研究的最后，我们将揭示如何以及 在成年和老年小鼠中风后，胶质瘢痕封闭病变，询问了参与 神经胶质瘢痕调节，其中几乎没有数据，而神经胶质瘤操纵这一途径，以改善 神经胶质瘢痕的屏障功能，从而防止中风后痴呆的发展。

PROJECT DESCRIPTION This project addresses patients' recovery from stroke and the development of post-stroke dementia, a sub- category of vascular dementia that affects approximately one-third of stroke sufferers. Following stroke, the blood brain barrier (BBB) is breached in the area of the lesion. As part of a cellular repair response, reactive astrocytes join together via an unknown mechanism to form a physical barrier to seal off the damaged area and protect the surviving neuropil. Astrogliosis and the formation of the glial scar is a critical component of the healing response to stroke. However, there have been no studies on the possibility that failure of the glial scar to perfectly seal the area of injury, which we recently demonstrated is also a site of chronic inflammatory responses, contributes to cognitive decline in patients that develop post-stroke dementia. This limitation has been due, in part, to the lack of an effective animal model of delayed cognitive dysfunction following stroke. However, we recently developed an innovative new mouse model of delayed cognitive dysfunction following stroke that models hallmarks of post-stroke dementia. Using this model, we now have substantial evidence that failure of the glial scar to segregate chronically leaky blood vessels within the lesion, as well as chronic inflammatory responses occurring in the lesion, is one cause of post-stroke dementia. Therefore the goals of this project are to determine for the first time precisely how (and how effectively) the glial scar seals the area of injury following stroke, by identifying the cellular and molecular mechanisms involved, and then to manipulate these mechanisms to enhance repair by the glial scar. These goals will be achieved by using our new mouse model of delayed cognitive dysfunction following stroke in conjunction with confocal and electron microscopy, immunohistochemistry, biochemical assays, flow cytometry, multiplex immunoassays, and behavioral studies, in adult and aged wildtype and transgenic mice. At the end of these studies we will have revealed how well the glial scar seals lesions following stroke in both adult and aged mice, interrogated a key pathway involved in glial scar regulation for which there is little data, and pharmacologically manipulated this pathway to improve the barrier function of the glial scar, and thereby protect against the development of post-stroke dementia.