Arachnoid barrier breakdown in bacterial meningitis

项目总结

Project Summary The central nervous system (CNS) is protected by two major barrier systems, the blood brain-barrier (BBB) and the blood-cerebrospinal fluid barrier (B-CSFB). These essential barrier systems each have unique cellular properties that tightly regulate the molecules and cells that can enter (or exit) the brain and the cerebrospinal fluid (CSF). CNS barriers are also vulnerable to breakdown in a variety of diseases, causing or exacerbating CNS pathology. The breakdown of the B-CSFB at the level of the meninges, a trilayered structure that surrounds the brain and spinal cord, is poorly understood. The critical B-CSFB structures of the meninges is the arachnoid barrier, a tight junction containing epithelial- like layer that segregates the outer meningeal dura and periphery from the inner leptomeninges and CSF. Unlike the BBB and other parts of the B-CSFB, there is very little known about the susceptibility of the arachnoid barrier to breakdown during disease. Here, I utilize Group B Streptococcus (GBS), a model of acute bacterial meningitis, in order to identify the cellular and molecular mechanisms of arachnoid barrier breakdown. I will leverage the combined knowledge of the Siegenthaler lab (experts in CNS vasculature and the BBB) as well as the Doran Lab (leaders in studying bacteria-host interactions during meningitis) in order to test the hypothesis that bacterial meningitis disrupts cellular barrier properties by driving Snail1-dependent Epithelial to Mesenchyme Transition (EMT), loss of tight and adherens junctions, and impaired functional barrier integrity. Furthermore, I will elucidate if GBS directly binds primary arachnoid barrier cells or if GBS exerts its effects through inflammatory cytokines. Completion of this work will substantially advance the field of CNS barrier systems by providing new tools to study arachnoid barrier function and a novel understanding of how the arachnoid barrier breaks down in disease. I will also generate a comprehensive model of arachnoid barrier cellular properties that can be investigated for breakdown in other diseases that involve the meninges. This new knowledge about the arachnoid barrier has the potential to be exploited to design new ways to limit crossing of molecules and cells at the arachnoid barrier to treat disease and will provide novel in vitro and in vivo approaches for understanding the B-CSFB during homeostasis and disease. Finally, the proposed goals of this fellowship will give me the conceptual, technical, and professional training necessary to develop myself as an independent researcher investigating the impact of CNS barriers on CNS health and neurological diseases.