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

小胶质细胞激活对中枢神经系统血脑屏障破坏的反应

• 批准号: 8361913
• 负责人: Katerina Akassoglou
• 金额: $ 0.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361913
• 关键词: Actins; Animal Model; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Glioblastoma; Cytoskeleton; DNA Sequence Rearrangement; Demyelinations; Deposition; Development; Extravasation; Fibrinogen; Funding; Grant; ITGAM gene; ITGB2 gene; Image; Image Analysis; In Vitro; Inflammatory; Integrins; Microglia; Microscopy; Molecular; Multiple Sclerosis; Mus; National Center for Research Resources; Nerve Regeneration; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neuroglia; Pathogenesis; Pathology; Peripheral Nerves; Phagocytosis; Principal Investigator; Process; Research; Research Infrastructure; Resources; Rupture; Signal Transduction; Site; Source; Spinal Cord; Spinal cord injury; Stroke; United States National Institutes of Health; Work; base; cost; in vivo; nervous system disorder; receptor; response; two-photon

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 microglial 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 in vivo 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 -crosstalk between blood factors and the brain parenchyma as it relates to glial cell activation and the development of CNS pathology.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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，抑制周围神经再生，并加剧MS动物模型中中枢神经系统的炎性脱髓鞘。本提案中的具体假设是，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的动物模型中，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使用小鼠脑和脊髓中的体内成像通过BBB破坏和纤维蛋白原渗漏直接证明小胶质细胞活化。由于BBB破坏和小胶质细胞活化是几种神经退行性疾病的标志，我们期望我们的工作提供血液因子和脑实质之间的分子串扰的最新证明，因为它涉及胶质细胞活化和CNS病理学的发展。