Modulation of Blood-Brain Barrier Defense and Dysfunction during Bacterial Meningitis

细菌性脑膜炎期间血脑屏障防御和功能障碍的调节

基本信息

  • 批准号:
    10091536
  • 负责人:
  • 金额:
    $ 42.69万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-02-01 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Bacterial meningitis is the most common serious infection of the central nervous system (CNS) and a major cause of death and disability worldwide, especially in children. Although antibiotic therapy has changed bacterial meningitis from a uniformly fatal disease to an often curable one, the overall outcome remains unfavorable, with mortality of 5 to 10% and permanent neurologic sequelae occurring in 5 to 40% of survivors, depending on patient age and pathogen. Disruption and dysfunction of the blood-brain barrier (BBB) is a hallmark event in the pathophysiology of bacterial meningitis. Little is known, however, about the very first and crucial interaction between a bacterial pathogen with the BBB that initiates this chain of events, and may ultimately determine a poor or favorable neurological outcome in meningitis patients. This proposal seeks to elucidate the molecular mechanisms of BBB disruption during bacterial infection, and why it fails as a neuroprotective barrier during bacterial meningitis. We have shown that bacterial infection induces an epithelial to mesenchymal transition (EMT) program in endothelial cells (EndoMT), disrupting tight junctions in BBB endothelium through the upregulation of host transcription factor Snail1, a global repressor of tight junctions. Further, we have discovered that a bacterial adhesin interacts directly with vimentin, an intermediate filament protein that is induced during EMT/EndoMT. I hypothesize that BBB disruption may be due to the combined effect of bacterial entry and modulation of host signaling pathways that results in compromised barrier function. Further that bacterial pathogens associated with CNS disease possess the unique ability to penetrate brain endothelium, which ultimately leads to BBB dysfunction. These hypotheses will be addressed with both in vitro and in vivo models of BBB penetration using Group B streptococcus (GBS) as a model human pathogen associated with meningitis. AIM 1: Characterize the bacterial determinant(s) that initiate Snail1 activation and the contribution of Snail1 to BBB breakdown during GBS meningitis; AIM 2: Characterize the host factors that contribute to Snail1 activation during GBS infection; AIM 3: Determine the contribution of GBS-vimentin interaction to BBB penetration and the development of meningitis. These studies should increase our understanding of the bacterial and host factors involved in the interaction with brain endothelium that leads to barrier disruption, pathogen transit into the brain, and disease progression.
项目摘要 细菌性脑膜炎是中枢神经系统(CNS)最常见的严重感染, 死亡和残疾的原因,特别是在儿童中。虽然抗生素治疗已经改变 细菌性脑膜炎从一种一致致命的疾病转变为一种通常可治愈的疾病, 不利,死亡率为5 - 10%,5 - 40%的幸存者发生永久性神经系统后遗症, 取决于患者年龄和病原体。血脑屏障(BBB)的破坏和功能障碍是一种 细菌性脑膜炎病理生理学的标志性事件。然而,人们对第一个和第二个世界知之甚少。 细菌病原体与BBB之间的关键相互作用,启动这一系列事件,并可能 最终确定脑膜炎患者的神经系统预后不良或良好。这项建议旨在 阐明细菌感染期间血脑屏障破坏的分子机制,以及为什么它不能作为一种有效的治疗方法。 细菌性脑膜炎期间的神经保护屏障。我们已经证明,细菌感染诱导上皮细胞 内皮细胞间质转化(EMT)程序(EndoMT),破坏BBB中的紧密连接 通过上调宿主转录因子Snail 1(一种紧密连接的全局阻遏物)来调节内皮细胞。 此外,我们还发现细菌粘附素与波形蛋白(一种中间丝)直接相互作用 在EMT/EndoMT期间诱导的蛋白。我推测血脑屏障破坏可能是由于 细菌进入的影响和宿主信号传导途径的调节,导致屏障功能受损。 此外,与CNS疾病相关的细菌病原体具有独特的穿透大脑的能力, 内皮细胞,最终导致BBB功能障碍。这些假设将在体外 以及使用B族链球菌(GBS)作为模型人类病原体的BB B渗透的体内模型 与脑膜炎有关。目的1:表征启动Snail 1激活的细菌决定簇, GBS脑膜炎期间Snail 1对BBB破坏的贡献; AIM 2:表征 GBS感染时Snail 1激活的作用;目的3:确定GBS-波形蛋白的作用 与BBB渗透和脑膜炎发展的相互作用。这些研究应该增加我们的 了解与脑内皮细胞相互作用的细菌和宿主因素, 屏障破坏、病原体转运进入脑和疾病进展。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Kelly S Doran其他文献

Kelly S Doran的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Kelly S Doran', 18)}}的其他基金

Determinants of polymicrobial diabetic wound infections
多种微生物糖尿病伤口感染的决定因素
  • 批准号:
    10665269
  • 财政年份:
    2023
  • 资助金额:
    $ 42.69万
  • 项目类别:
Colorado Immunology and Microbiology Conference (CIMC)
科罗拉多州免疫学和微生物学会议(CIMC)
  • 批准号:
    10751556
  • 财政年份:
    2023
  • 资助金额:
    $ 42.69万
  • 项目类别:
Roles of novel cationic lipids in bacterial pathogenesis
新型阳离子脂质在细菌发病机制中的作用
  • 批准号:
    10732462
  • 财政年份:
    2023
  • 资助金额:
    $ 42.69万
  • 项目类别:
2022 Streptococcal Biology Gordon Research Conference and Gordon Research Seminar
2022年链球菌生物学戈登研究大会暨戈登研究研讨会
  • 批准号:
    10462952
  • 财政年份:
    2022
  • 资助金额:
    $ 42.69万
  • 项目类别:
Calprotectin modulates Group B streptococcal colonization and disease
钙卫蛋白调节 B 族链球菌定植和疾病
  • 批准号:
    10190492
  • 财政年份:
    2021
  • 资助金额:
    $ 42.69万
  • 项目类别:
Host and bacterial mechanisms governing Group B streptococcal persistence in the female genital tract
控制 B 族链球菌在女性生殖道中持续存在的宿主和细菌机制
  • 批准号:
    10219491
  • 财政年份:
    2021
  • 资助金额:
    $ 42.69万
  • 项目类别:
Calprotectin modulates Group B streptococcal colonization and disease
钙卫蛋白调节 B 族链球菌定植和疾病
  • 批准号:
    10373060
  • 财政年份:
    2021
  • 资助金额:
    $ 42.69万
  • 项目类别:
Host and bacterial mechanisms governing Group B streptococcal persistence in the female genital tract
控制 B 族链球菌在女性生殖道中持续存在的宿主和细菌机制
  • 批准号:
    10363740
  • 财政年份:
    2021
  • 资助金额:
    $ 42.69万
  • 项目类别:
Host and bacterial mechanisms governing Group B streptococcal persistence in the female genital tract
控制 B 族链球菌在女性生殖道中持续存在的宿主和细菌机制
  • 批准号:
    10754833
  • 财政年份:
    2021
  • 资助金额:
    $ 42.69万
  • 项目类别:
Host and bacterial mechanisms governing Group B streptococcal persistence in the female genital tract
控制 B 族链球菌在女性生殖道中持续存在的宿主和细菌机制
  • 批准号:
    10763095
  • 财政年份:
    2021
  • 资助金额:
    $ 42.69万
  • 项目类别:

相似海外基金

Developing a Young Adult-Mediated Intervention to Increase Colorectal Cancer Screening among Rural Screening Age-Eligible Adults
制定年轻人介导的干预措施,以增加农村符合筛查年龄的成年人的结直肠癌筛查
  • 批准号:
    10653464
  • 财政年份:
    2023
  • 资助金额:
    $ 42.69万
  • 项目类别:
Doctoral Dissertation Research: Estimating adult age-at-death from the pelvis
博士论文研究:从骨盆估算成人死亡年龄
  • 批准号:
    2316108
  • 财政年份:
    2023
  • 资助金额:
    $ 42.69万
  • 项目类别:
    Standard Grant
Determining age dependent factors driving COVID-19 disease severity using experimental human paediatric and adult models of SARS-CoV-2 infection
使用 SARS-CoV-2 感染的实验性人类儿童和成人模型确定导致 COVID-19 疾病严重程度的年龄依赖因素
  • 批准号:
    BB/V006738/1
  • 财政年份:
    2020
  • 资助金额:
    $ 42.69万
  • 项目类别:
    Research Grant
Transplantation of Adult, Tissue-Specific RPE Stem Cells for Non-exudative Age-related macular degeneration (AMD)
成人组织特异性 RPE 干细胞移植治疗非渗出性年龄相关性黄斑变性 (AMD)
  • 批准号:
    10294664
  • 财政年份:
    2020
  • 资助金额:
    $ 42.69万
  • 项目类别:
Sex differences in the effect of age on episodic memory-related brain function across the adult lifespan
年龄对成人一生中情景记忆相关脑功能影响的性别差异
  • 批准号:
    422882
  • 财政年份:
    2019
  • 资助金额:
    $ 42.69万
  • 项目类别:
    Operating Grants
Modelling Age- and Sex-related Changes in Gait Coordination Strategies in a Healthy Adult Population Using Principal Component Analysis
使用主成分分析对健康成年人群步态协调策略中与年龄和性别相关的变化进行建模
  • 批准号:
    430871
  • 财政年份:
    2019
  • 资助金额:
    $ 42.69万
  • 项目类别:
    Studentship Programs
Transplantation of Adult, Tissue-Specific RPE Stem Cells as Therapy for Non-exudative Age-Related Macular Degeneration AMD
成人组织特异性 RPE 干细胞移植治疗非渗出性年龄相关性黄斑变性 AMD
  • 批准号:
    9811094
  • 财政年份:
    2019
  • 资助金额:
    $ 42.69万
  • 项目类别:
Study of pathogenic mechanism of age-dependent chromosome translocation in adult acute lymphoblastic leukemia
成人急性淋巴细胞白血病年龄依赖性染色体易位发病机制研究
  • 批准号:
    18K16103
  • 财政年份:
    2018
  • 资助金额:
    $ 42.69万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Doctoral Dissertation Research: Literacy Effects on Language Acquisition and Sentence Processing in Adult L1 and School-Age Heritage Speakers of Spanish
博士论文研究:识字对西班牙语成人母语和学龄传统使用者语言习得和句子处理的影响
  • 批准号:
    1823881
  • 财政年份:
    2018
  • 资助金额:
    $ 42.69万
  • 项目类别:
    Standard Grant
Adult Age-differences in Auditory Selective Attention: The Interplay of Norepinephrine and Rhythmic Neural Activity
成人听觉选择性注意的年龄差异:去甲肾上腺素与节律神经活动的相互作用
  • 批准号:
    369385245
  • 财政年份:
    2017
  • 资助金额:
    $ 42.69万
  • 项目类别:
    Research Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了