FOCAL ADHESION KINASE ACTIVATION IN THE BLOOD-BRAIN BARRIER

血脑屏障中的局部粘附激酶激活

• 批准号: 8172964
• 负责人: ANDREW G MACLEAN
• 金额: $ 6.18万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172964
• 关键词: Blood - brain barrier anatomy; Brain; Cells; Cerebrum; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Encephalitis; Endothelial Cells; Focal Adhesion Kinase 1; Funding; Grant; HIV encephalitis; In Vitro; Institution; Mediating; Microglia; Modeling; Molecular; Myosin Light Chain Kinase; Neurologic; Phosphorylation; Proteins; Research; Research Personnel; Resources; Signal Pathway; Source; Subfamily lentivirinae; Tight Junctions; Time; United States National Institutes of Health; Virus; in vivo; inhibitor/antagonist; interest; macrophage; prevent

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. Expression of tight junction proteins between brain microvascular endothelial cells (MBEC) of the blood-brain barrier (BBB) is lost during development of HIV encephalitis (HIVE). While many studies have focused on the strains of virus that induce neurological sequelae or on the macrophages/microglia that are associated with the development of encephalitis, the molecular signaling pathways within the BMECs involved have yet to be resolved. We have previously shown that there is activation and disruption of an in vitro BBB model using lentivirus-infected CEMx174 cells. We and others have shown similar disruption in vivo. Therefore, it was of interest to determine of the presence of infected primary macrophages could disrupt intact cerebral microvessels immediately ex vivo, and if so, which signaling pathways were involved. Our data demonstrate that disruption of tight junctions between BMECs is mediated through activation of focal adhesion kinase (FAK) by phosphorylation at TYR-397. We also show that myosin light chain kinase (MLCK) is also phosphorylated in the same time course as FAK. Inhibition of FAK activation is sifficient to prevent tight junction disruption. This, it may be possible to inhibit the development of HIVE by using inhibitors of FAK and MLCK.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此，可以在其他清晰的条目中表示。列出的机构是 对于中心，这不一定是调查员的机构。 在HIV脑炎（HIVE）发育过程中，脑脑屏障（BBB）的脑微血管内皮细胞（MBEC）之间紧密连接蛋白的表达损失。 尽管许多研究集中在诱导神经后遗症或与脑炎发展相关的巨噬细胞/小胶质细胞的病毒菌株上，但涉及BMEC中的分子信号通路尚未解决。 我们先前已经表明，使用慢病毒感染的CEMX174细胞会激活和破坏体外BBB模型。 我们和其他人在体内表现出类似的破坏。 因此，确定受感染的原发性巨噬细胞的存在可能会破坏立即离体的完整脑微血管，如果是这样，则涉及哪些信号通路。 我们的数据表明，BMEC之间紧密连接的破坏是通过在Tyr-397上通过磷酸化激活局灶性粘附激酶（FAK）来介导的。 我们还表明，肌球蛋白轻链激酶（MLCK）在与FAK的同一时间过程中也被磷酸化。 FAK激活的抑制是可防止紧密连接破坏的粒状。这是可以通过使用FAK和MLCK的抑制剂来抑制Hive的发育。