The role of the brain endothelium in fungal infections of the CNS

脑内皮在中枢神经系统真菌感染中的作用

基本信息

  • 批准号:
    8656819
  • 负责人:
  • 金额:
    $ 18.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-05-01 至 2016-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): There is a critical gap in our understanding of how a deadly fungal pathogen such as Cryptococcus neoformans invades the central nervous system (CNS). The continued existence of this gap has resulted in a major deficit in our grasp of fungal disease of the CNS and has led to a shortfall in the development of more effective and innovative treatment options. Current evidence on cerebral pathogenesis of C. neoformans has shown a predominantly transcellular migration of cryptococci across the brain endothelium (a.k.a. the blood- brain barrier); but the identities of brain endothelium factors and key virulenc fungal factors that promote this process are largely unknown. The objective in this particular application is to understand how a newly identified, secreted fungal metalloprotease targets brain endothelial proteins and how this association transforms the microenvironment within the fungal-brain endothelium interface to promote the migration of fungal cells into the CNS. The central hypothesis is that a newly identified secreted metalloprotease (Mpr1) stimulates the transmigration of cryptococci into the CNS by unmasking/stimulating surface receptors/ligands and/or adhesion proteins via its proteolytic activity. The formulation of this hypothesis is based on strong preliminary data produced from the laboratory of the applicant. The rationale for the proposed research is that understanding the molecular mechanisms that induce cerebral pathogenesis of C. neoformans will translate into the development of advanced antinfective drugs and vaccines that could be highly effective in the treatment of cryptococcal disease which claims the lives of ~600,00 individuals per year. Guided by strong preliminary data, this hypothesis will be tested by pursuing one specific aim: Resolve the role of the brain endothelium in the transmigration of C. neoformans into the CNS by identifying the host targets of Mpr1 that transform the surface microenvironment at the fungal-brain endothelium interface. Here we will test the prediction that Mpr1 directly targets surface proteins of the brain endothelium as a means to redefine the microenvironment of the fungal-brain endothelium to favor and promote fungal invasion of the CNS. We will do this by first establishing whether Mpr1 is sufficient for attachment to the brain endothelium by expressing Mpr1 in a non-pathogenic yeast and exploiting this phenotype to identify host targets of Mpr1. Secondly we will use a powerful, high-content proteomic screen to identify native host substrates of Mpr1. To prioritize and resolve the role of these targets, an in vitro model of the BBB, in vivo models of cryptococcal disease and real-time intravital microscopy will be utilized. The innovation of the proposed study lies in its use of an in vitro model of the BBB and state-of-the-art methodology to examine a novel mechanism utilized by C. neoformans to swarm the CNS. We anticipate that the proposed study will advance our understanding of the role of the brain endothelium in fungal disease of the CNS. Ultimately such knowledge has the potential to invigorate drug and vaccine development strategies for individuals suffering from fungal meningoencephalitis.
描述(由申请人提供):我们对新型隐球菌等致命真菌病原体如何侵入中枢神经系统(CNS)的理解存在严重差距。这种差距的持续存在导致我们对中枢神经系统真菌病的了解严重不足,并导致开发更有效和创新的治疗方案的能力不足。目前关于新型隐球菌脑发病机制的证据表明,隐球菌主要通过脑内皮(又称血脑屏障)进行跨细胞迁移;但促进这一过程的脑内皮因子和关键毒力真菌因子的身份在很大程度上尚不清楚。该特定应用的目的是了解新鉴定的分泌型真菌金属蛋白酶如何靶向脑内皮蛋白,以及这种关联如何改变真菌-脑内皮界面内的微环境以促进真菌细胞迁移到中枢神经系统。中心假设是,一种新发现的分泌型金属蛋白酶 (Mpr1) 通过其蛋白水解活性揭示/刺激表面受体/配体和/或粘附蛋白,从而刺激隐球菌迁移到 CNS 中。该假设的提出是基于申请人实验室产生的强有力的初步数据。拟议研究的基本原理是,了解诱导新型隐球菌脑部发病机制的分子机制将转化为先进抗感染药物和疫苗的开发,这些药物和疫苗可以非常有效地治疗隐球菌疾病,该疾病夺去了约 600 人的生命,每年 00 人。在强有力的初步数据的指导下,这一假设将通过追求一个特定目标进行检验:通过识别 Mpr1 的宿主靶点来解决脑内皮在新型隐球菌迁移到中枢神经系统中的作用,从而改变真菌的表面微环境。脑内皮界面。在这里,我们将测试 Mpr1 直接靶向脑内皮表面蛋白的预测,作为重新定义真菌脑内皮微环境的手段,以有利于和促进真菌入侵中枢神经系统。我们将首先通过在非致病性酵母中表达 Mpr1 并利用这种表型来识别 Mpr1 的宿主靶点来确定 Mpr1 是否足以附着在脑内皮上。其次,我们将使用强大的高内涵蛋白质组筛选来鉴定 Mpr1 的天然宿主底物。为了优先考虑并解决这些目标的作用,将利用 BBB 体外模型、隐球菌疾病体内模型和实时活体显微镜。这项研究的创新之处在于它使用了 BBB 体外模型和最先进的方法来研究新型隐球菌用来聚集中枢神经系统的新机制。我们预计拟议的研究将增进我们对脑内皮在中枢神经系统真菌病中作用的理解。最终,这些知识有可能激发针对真菌性脑膜脑炎患者的药物和疫苗开发策略。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Metalloprotease, Mpr1, Engages AnnexinA2 to Promote the Transcytosis of Fungal Cells across the Blood-Brain Barrier.
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ANGIE GELLI其他文献

ANGIE GELLI的其他文献

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{{ truncateString('ANGIE GELLI', 18)}}的其他基金

Project 2: Protection of Blood-Brain Barrier Function
项目二:血脑屏障功能保护
  • 批准号:
    10684086
  • 财政年份:
    2022
  • 资助金额:
    $ 18.31万
  • 项目类别:
Antifungal activity of amyloid beta as a driver of dementia and AD pathogenesis.
β 淀粉样蛋白的抗真菌活性是痴呆和 AD 发病机制的驱动因素。
  • 批准号:
    10711875
  • 财政年份:
    2020
  • 资助金额:
    $ 18.31万
  • 项目类别:
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:
    10552625
  • 财政年份:
    2020
  • 资助金额:
    $ 18.31万
  • 项目类别:
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:
    10330006
  • 财政年份:
    2020
  • 资助金额:
    $ 18.31万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 18.31万
  • 项目类别:
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:
    10604215
  • 财政年份:
    2020
  • 资助金额:
    $ 18.31万
  • 项目类别:
Vascular Inflammation and Exosomes as Mediators in Aging and Dementia
血管炎症和外泌体作为衰老和痴呆症的介质
  • 批准号:
    9920606
  • 财政年份:
    2018
  • 资助金额:
    $ 18.31万
  • 项目类别:
The role of the brain endothelium in fungal infections of the CNS
脑内皮在中枢神经系统真菌感染中的作用
  • 批准号:
    8584102
  • 财政年份:
    2013
  • 资助金额:
    $ 18.31万
  • 项目类别:
Fungal calcium channels as therapeutic targets for AIDS-associated opportunistic
真菌钙通道作为艾滋病相关机会性感染的治疗靶点
  • 批准号:
    8015377
  • 财政年份:
    2009
  • 资助金额:
    $ 18.31万
  • 项目类别:
Fungal calcium channels as therapeutic targets for AIDS-associated opportunistic
真菌钙通道作为艾滋病相关机会性感染的治疗靶点
  • 批准号:
    7683423
  • 财政年份:
    2009
  • 资助金额:
    $ 18.31万
  • 项目类别:

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  • 批准号:
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HIV感染并发糖尿病的血脑屏障损伤:预防认知障碍的机制和保护策略
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The role of the brain endothelium in fungal infections of the CNS
脑内皮在中枢神经系统真菌感染中的作用
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  • 财政年份:
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    $ 18.31万
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淀粉样蛋白B肽对内皮粘附及其相关细胞通路的影响
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