MICROGLIA ACTIVATION IN RESPONSE TO BLOOD-BRAIN BARRIER DISRUPTION IN THE CNS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 血脑屏障破坏是与血管破裂相关的神经系统疾病的标志，如中风、多发性硬化症(MS)、脑胶质母细胞瘤和脊髓损伤。然而，血液成分在中枢神经系统发病机制中的分子和细胞机制尚不清楚。我们以前的研究发现，血脑屏障破坏后沉积在神经系统的主要血液因子纤维蛋白原抑制周围神经再生，并加剧中枢神经系统的炎性脱髓鞘。本研究的具体假设是，血脑屏障破坏导致纤维蛋白原在中枢神经系统内泄漏，导致小胶质细胞激活。我们的假说基于以下观察：1.使用双光子显微镜，小胶质细胞通过突起延伸和分离损伤部位对脑和脊髓血管损伤做出非常快速的反应；2.纤维蛋白原通过CD11b/CD18整合素受体的信号在体外激活小胶质细胞，导致肌动蛋白细胞骨架的动态重排，从而增加吞噬作用；3.体内纤维蛋白原耗竭导致多发性硬化症动物模型中小胶质细胞激活减少。基于这些观察，本建议的实验重点是通过在小鼠脑和脊髓中的实时成像直接演示BBB破坏和纤维蛋白原渗漏引起的小胶质细胞激活。由于血脑屏障破坏和小胶质细胞激活是几种神经退行性疾病的标志，我们希望我们的工作能为分子链接/串扰提供最先进的演示。在血液内容物之间？因素？和脑实质，因为它与神经胶质细胞的激活有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Blood-brain barrier disruption is a hallmark of nervous system diseases associated with vascular rupture, such as stroke, multiple sclerosis (MS), brain glioblastomas and spinal cord injury. However, the molecular and cellular mechanism of the contribution of blood components to CNS pathogenesis remains poorly understood. Our previous studies identified that fibrinogen, a major blood factor deposited in the nervous system after BBB disruption, inhibits peripheral nerve regeneration and exacerbates inflammatory demyelination in the central nervous system in an animal model for MS. The specific hypothesis in this proposal is that BBB disruption that leads to leakage of fibrinogen in the CNS is responsible for microglia activation. Our hypothesis is based on the observations that: 1. Using two-photon microscopy, microglia respond very rapidly by process extension and isolation of the traumatized sites to blood vessel damage in both the brain and spinal cord; 2. Fibrinogen activates microglia in vitro via signaling through the CD11b/CD18 integrin receptor resulting in a dynamic rearrangement of the actin cytoskeleton resulting to increase in phagocytosis; 3. Fibrinogen depletion in vivo results in decreased microglial activation in an animal model for MS. Based on these observations, the experimental focus of this proposal is on the direct demonstration of microglial activation by BBB disruption and fibrinogen leakage using live imaging in the mouse brain and spinal cord. Since BBB disruption and microglial activation are hallmarks for several neurodegenerative diseases, we expect our work to provide a state-of-the-art demonstration of the molecular link/crosstalk? between blood contents? factors? and brain parenchyma as it relates to glial cell activation.