Impairment of the cerebral vasculature during bacterial meningitis

细菌性脑膜炎期间脑血管系统受损

• 批准号: 10795568
• 负责人: Brandon Jonathan Kim
• 金额: $ 44.7万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10795568
• 关键词: ABCB1 gene; Alabama; Attenuated; Bacteria; Bacterial Meningitis; Bacterial Transformation; Biological Assay; Birth; Blood - brain barrier anatomy; Brain; Candidate Disease Gene; Cell Line; Cell model; Cells; Central Nervous System; Central Nervous System Infections; Cerebrovascular system; Complication; Data; Data Analyses; Disease; Down-Regulation; Drug Efflux; Education; Endocytosis; Endocytosis Pathway; Endothelial Cells; Environment; Exhibits; Failure; Goals; Homeostasis; Human; Impairment; In Vitro; Infection; Intervention; Invaded; Knock-out; Left; Libraries; Life; Measures; Medical; Meningeal; Meningitis; Modeling; Modernization; Mus; Neonatal meningitis; Nervous System Trauma; Nutrient; Pathway interactions; Penetration; Peripheral; Phenotype; Pinocytosis; Poison; Property; Regulation; Research Personnel; Role; STEM field; Signal Pathway; Signal Transduction; Stains; Streptococcal Infections; Streptococcus Group B; Stroke; Students; Survivors; Techniques; Technology; Testing; Tissues; Toxin; Translating; Universities; Virulence Factors; Western Blotting; Work; blood cerebrospinal fluid barrier; brain endothelial cell; cytokine; extracellular; gene discovery; gene product; human stem cells; in vivo; inhibitor; loss of function; meetings; mouse model; mutant; nervous system disorder; novel therapeutic intervention; overexpression; pathogen; pharmacologic; stem cell model; symposium; synergism; undergraduate research; undergraduate student; uptake

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.

项目摘要 细菌性脑膜炎是中枢神经系统（CNS）严重威胁生命的感染 当细菌能够越过高度专业的脑内皮细胞（BEC）并进入 脑。而现代的医疗干预已从统一致命的 疾病，许多幸存者表现出永久的神经系统损害。在 细菌性脑膜炎是中风。中枢神经系统受到血脑屏障（BBB）和脑膜的保护 由BEC组成并构成血液 大脑中的血管。与周围内皮细胞相比，BEC表现出独特的特性 这有助于障碍功能并支持适当的大脑稳态。但是，在细菌期间 脑膜炎，BEC无法保护大脑。这项研究的目的是使用最先进的 人类干细胞建模技术，以评估BEC如何无法保持其独特性能 并保护细菌性脑膜炎期间的大脑。在AIM 1中，我们将探讨B组链球菌如何 （GBS）改变健康中关闭的细胞摄取途径内吞作用和生皮细胞增多症 BEC，以及这如何有助于GBS入侵BEC和向脑膜炎发展。在AIM 2中，我们 已经发现GB可以破坏外排转运蛋白P-糖蛋白（PGP），我们将发现 宿主细胞信号导致PGP破坏并确定负责的GBS因子。协同作用 目的之间存在，因为既质疑BEC的独特属性，又是它们在期间的失败 疾病。我们的目标将确定感染过程中BEC失败的机制，但对 许多神经系统疾病，可能会发现新型治疗干预措施的途径。