Impairment of the cerebral vasculature during bacterial meningitis

项目摘要 细菌性脑膜炎是一种严重威胁生命的中枢神经系统(CNS)感染 当细菌能够穿过高度专业化的脑内皮细胞(BECs)进入 大脑。虽然现代医学干预已经将细菌性脑膜炎从一致致命的 许多幸存者表现出永久性的神经损伤。过程中的一个主要并发症 细菌性脑膜炎是中风。中枢神经系统受到血脑屏障和脑膜的保护。 血-脑脊液屏障(MBCSFB)，由BEC组成，构成血液 大脑中的血管。与外周内皮细胞相比，BEC表现出独特的特性 这有助于屏障功能和支持适当的大脑稳态。然而，在细菌 脑膜炎，脑脊液无法保护大脑。这项研究的目标是使用最先进的 评估BEC如何未能保持其独特特性的人类干细胞建模技术 并在细菌性脑膜炎期间保护大脑。在目标1中，我们将探索B组链球菌是如何 (GBS)改变健康人体内关闭的细胞摄取途径、内吞作用和胞饮作用 BECs，以及这如何促进BECs的GBS入侵和发展为脑膜炎。在目标2中，我们 已经发现GBS可以干扰外流转运体P-糖蛋白(Pgp)，我们将发现 导致PGP中断的宿主细胞信号，并确定相关的GBS因素。协同效应 两个目标之间的存在是因为两者都询问了BEC的独特属性以及它们在 疾病。我们的目标将确定感染过程中BEC失败的机制，但对 许多神经疾病，并可能发现新的治疗干预措施的途径。

Project Summary Bacterial meningitis is a serious life-threatening infection of the central nervous system (CNS) that occurs when bacteria are able to cross highly specialized brain endothelial cells (BECs) and enter the brain. While modern medical intervention has transformed bacterial meningitis from a uniformly fatal disease, many survivors exhibit permanent neurological damage. One major complication during bacterial meningitis is stroke. The CNS is protected by the blood-brain barrier (BBB) and meningeal blood-cerebrospinal fluid barrier (mBCSFB), that are comprised of BECs and make up the blood vessels in the brain. When compared with peripheral endothelial cells, BECs exhibit unique properties that contribute to barrier function and support proper brain homeostasis. However, during bacterial meningitis, BECs fail to protect the brain. The goal of this study is to use the most state-of-the-art human stem-cell modeling techniques to assess how BECs fail to maintain their unique properties and protect the brain during bacterial meningitis. In Aim 1 we will explore how Group B Streptococcus (GBS) alters the cellular uptake pathways endocytosis and pinocytosis that is shut off in healthy BECs, and how this contributes to GBS invasion of BECs and progression to meningitis. In Aim 2, we have discovered that GBS can disrupt the efflux transporter P-glycoprotein (Pgp), we will discover the host cell signaling that contributes to Pgp disruption and identify the GBS factor responsible. Synergy between aims exists because both interrogate unique properties of BECs and how they fail during disease. Our aims will determine mechanisms of BEC failure during infection yet have implications in many neurological disorders and may uncover avenues for novel therapeutic interventions.