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）是一种高度限制性和选择性的结构，可以保护 一些病原体，例如新型隐球菌 (Cn)，具有中枢神经系统 (CNS) 的特征。 通过真菌孢子的机制设法克服 BBB。 在我们的环境中普遍存在，我们在吸入雾化孢子后就会被感染 土壤、某些类型的树木和鸽子粪便中的 Cn 孢子一旦被吸入，就会在其中增殖。 肺组织，由于其高度亲神经性，可传播至中枢神经系统。 中枢神经系统中真菌细胞的观察结果已在尸检中实时报告，我们仍然 不完全了解大脑内皮细胞的分子相互作用或 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 与父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整体大脑健康的影响，而家长资助的重点是。 关于 EphA2-RTK 作为 Cn 渗入 CNS 介质的作用，补充研究 这里提出的将研究 BBB 中的跨细胞-旁细胞串扰如何有利于 真菌病原体跨 BBB 的渗透 目的将检验以下假设： 穿过 BBB 的细胞旁通路有助于 Cn 渗入 CNS Cn 诱导细胞骨架重塑的结果。 具体目标 1 将检查转胞吞作用和旁细胞路径的开放是否 通常在健康大脑中相互关联或共同调节，或者病原体是否可以选择性激活两者 途径。 具体目标 2 将涉及离体研究，以确定病原体是否会破坏紧密的稳定 连接并诱导伴随的细胞旁开放。拟议的研究将有一个直接的。 对开发预防神经感染的新疗法和设计新疗法的影响 旨在跨越 BBB 将货物传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 Amelia Bennett 对神经科学特别感兴趣， 神经感染，并受到激励加入我的实验室，以便她可以研究分子 驱动人类真菌病原体 Cn 进入中枢神经系统 (CNS) 的机制。 尽管发病率和死亡率很高，但该领域的研究尚未充分 通过这个项目，阿米莉亚将获得与真菌性脑膜脑炎相关的专业知识。 神经感染并利用它来建立一个利基市场，使她在她的领域具有竞争力 该项目是专门为加强阿米莉亚的参与而设计的。 生物医学研究，为阿米莉亚提供成功职业生涯所需的研究技能 一名独立科学家，并为阿米莉亚提供专业的职业培训，使她能够 她将成为学术界生物医学领域的研究员、教育家和导师。