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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 血脑屏障破坏是与血管破裂相关的神经系统疾病的标志，例如中风、多发性硬化症（MS）、脑胶质母细胞瘤和脊髓损伤。然而，血液成分对CNS发病机制的分子和细胞机制仍然知之甚少。我们以前的研究确定，血脑屏障破坏后沉积在神经系统中的主要血液因子纤维蛋白原，在MS的动物模型中抑制外周神经再生并加剧中枢神经系统中的炎性脱髓鞘。该提议中的具体假设是，血脑屏障破坏导致CNS中纤维蛋白原的泄漏是小胶质细胞活化的原因。我们的假设是基于以下观察：1。使用双光子显微镜，小胶质细胞通过过程延伸和创伤部位的隔离对脑和脊髓中的血管损伤做出非常迅速的反应; 2.纤维蛋白原通过CD 11b/CD 18整联蛋白受体的信号传导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，从而导致吞噬作用的增加; 3.在MS动物模型中，体内纤维蛋白原耗竭导致小胶质细胞活化减少。基于这些观察结果，本提案的实验重点是在小鼠脑和脊髓中使用实时成像通过BBB破坏和纤维蛋白原渗漏直接证明小胶质细胞活化。由于血脑屏障破坏和小胶质细胞活化是几种神经退行性疾病的标志，我们希望我们的工作提供一个国家的最先进的演示分子连接/串扰？血液成分之间的联系因素？和脑实质，因为它涉及神经胶质细胞活化和CNS病理学的发展。

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 and the development of CNS pathology.