The molecular basis for the translocation of fungi from blood-to-brain.

真菌从血液转移到大脑的分子基础。

• 批准号: 10572996
• 负责人: ANGIE GELLI
• 金额: $ 3.13万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572996
• 关键词: Academia; Address; Amelia; Area; Autopsy; Binding; Biomedical Research; Blood; Blood - brain barrier anatomy; Brain; Cells; Central Nervous System Fungal Infections; Columbidae; Cryptococcus neoformans; Cytoskeleton; Drops; Endothelium; Environment; Fungal Spores; Goals; Health; Human; Infection; Infiltration; Inhalation; Link; Mediating; Mediator of activation protein; Meningoencephalitis; Mentors; Mission; Molecular; Morbidity - disease rate; Movement; Nature; Neuraxis; Neurosciences; Pathway interactions; Proliferating; Reporting; Reproduction spores; Research; Research Personnel; Research Project Grants; Role; Science; Scientist; Soil; Structure; Structure of parenchyma of lung; Technology; Testing; Tight Junctions; Time; Training; Trees; United States National Institutes of Health; aerosolized; blood-brain barrier crossing; brain health; career; design; fungus; improved; interest; mortality; neurotropic; novel strategies; novel therapeutics; parent grant; parent project; pathogen; pathogenic fungus; prevent; skills; transcytosis

PROJECT ABSTRACT The blood-brain barrier (BBB) is a highly-restrictive and selective structure that protects the central nervous system (CNS). A few pathogens, such as Cryptococcus neoformans (Cn), have managed to overcome the BBB by mechanisms that are still largely unknown. Fungal spores are prevalent in our environment and we become infected following inhalation of aerosolized spores from soil, certain types of trees and pigeon droppings. Once inhaled, spores of Cn proliferate in lung tissue and due to their highly neurotropic nature, disseminate to the CNS. Although observations of fungal cells in the CNS have been reported in real-time and at autopsy, we still do not fully understand the molecular interactions at the brain endothelium or the pathways that mediate the movement of pathogens into the CNS. The proposed research project will address 2 specific aims that are fundamentally different from the parent project but importantly, they address the over-arching goal which is to resolve the molecular mechanisms that define the infiltration of Cn into the CNS and the subsequent effect on over-all brain health. While the parent grant focuses on the role of EphA2-RTK as a mediator of Cn infiltration into the CNS, the supplement study proposed here will examine how a transcellular-paracellular cross-talk in the BBB can favor the infiltration of fungal pathogens across the BBB. The aims will test the hypothesis that a paracellular pathway across the BBB contributes to the infiltration of Cn into the CNS as a consequence of cytoskeleton remodeling induced by Cn. Specific aim 1 will examine whether transcytosis and the opening of a paracellular path are normally linked or co-regulated in healthy brains or if pathogens can selectively activate both pathways. Specific aim 2 will involve ex-vivo studies to determine whether pathogens can destabilize tight junctions and induce a concomitant paracellular opening. The proposed studies will have a direct impact on developing new therapeutics that could prevent neuroinfections and on designing novel strategies for technologies geared toward crossing the BBB to deliver cargo to the brain. The proposed project is intended as a supplement to promote diversity in the biomedical sciences. The supplement candidate, Amelia Bennett, has a strong interest in neuroscience specifically, neuroinfections, and was motivated to join my lab so that she could study the molecular mechanisms that drive a human fungal pathogen, Cn, into the central nervous system (CNS). This area of research is understudied despite the significant morbidity and mortality that is associated with fungal meningoencephalitis. Through this project Amelia will acquire expertise in neuroinfections and use this to establish a niche that will allow her to be competitive in her research career. The project has been specifically designed to enhance Amelia’s participation in biomedical research, to provide Amelia with the research skills needed for a successful career as an independent scientist and to provide Amelia with the professional career training that will allow her to thrive as a researcher, educator and mentor in biomedical sciences in academia.

项目摘要 血脑屏障（BBB）是一种高度限制和选择性的结构，可保护 中枢神经系统（CNS）。一些病原体，例如新隐球菌（CN），具有 设法通过仍然未知的机制克服了BBB。真菌孢子是 在我们的环境中普遍存在，并在吸入气溶胶孢子后被感染 从土壤中，某些类型的树木和鸽子粪便。一旦继承，CN的孢子在 肺组织和由于其高度神经性的性质，向CNS传播。虽然 已实时报道了中枢神经系统中真菌细胞的观察，在尸检时，我们仍然 不要完全了解脑内皮的分子相互作用或 介导病原体进入中枢神经系统的运动。拟议的研究项目将解决2 与母公司项目根本不同的具体目标，但重要的是，它们解决了 总体目标是解决定义渗透的分子机制 CN进入中枢神经系统以及随后对所有大脑健康的影响。父母赠款专注于 关于Epha2-RTK作为CN中CNS中CN的介体的作用，补充研究 此处提出的将检查BBB中的跨细胞细胞交叉言论如何有利于 跨BBB的真菌病原体浸润。目的将检验以下假设 跨BBB的细胞细胞途径有助于将CN渗入CNS作为A CN诱导的细胞骨架重塑的结果。 特定的目标1将检查跨经细胞增多症和副细胞路径的开放是否是 通常在健康的大脑中连接或共同调节，或者病原体可以选择性地激活两者 途径。 特定的目标2将涉及前体研究，以确定病原体是否会破坏稳定 连接并引起伴随的细胞开口。拟议的研究将直接 对开发新疗法的影响，这些疗法可以防止神经感染和设计小说 旨在越过BBB将货物运送到大脑的技术策略。 拟议的项目旨在作为促进生物医学多样性的补充。 补充候选人阿米莉亚·贝内特（Amelia Bennett）特别对神经科学有浓厚的兴趣 神经感染，并被融合以加入我的实验室，以便她可以研究分子 将人类真菌病原体CN的机制驱逐到中枢神经系统（CNS）。 尽管发病率和死亡率很高，但仍能理解这一研究领域 与真菌脑膜脑炎有关。通过这个项目，阿米莉亚将获得专业知识 神经感染并用它来建立一个可以使她在她身上竞争的利基市场 研究职业。该项目是专门设计的，以增强Amelia的参与 生物医学研究，为Amelia提供成功职业所需的研究技能 独立科学家，为阿米莉亚（Amelia）提供职业培训，这将允许 她在学术界的生物医学科学领域的研究人员，教育者和心理蓬勃发展。