Effects of Neuroinflammation on Gap Junction Communication in Glia

神经炎症对神经胶质细胞间隙连接通讯的影响

基本信息

  • 批准号:
    7633772
  • 负责人:
  • 金额:
    $ 3.14万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-07-01 至 2011-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Gap junctions represent direct intercellular conduits between contacting cells that permit the passage of small molecules (> 1 kDa) including ions, metabolic precursors, and second messengers. The observation of extensive intercellular coupling and large numbers of gap junctions in the central nervous system (CNS) suggests a syncytium-like organization of glial compartments. One CNS infectious disease in which nothing is known regarding its impact on glial gap junction communication (GJC) is parenchymal infection with pyogenic bacteria leading to the establishment of brain abscess. Recent studies have revealed that several proinflammatory mediators detected in developing brain abscesses and produced by S. aureus activated glia, including interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-a), and nitric oxide (NO) are capable of modulating GJC in astrocytes and microglia. Specifically, these molecules attenuate GJC in astrocytes whereas activated microglia become functionally coupled. We have coined this phenomenon a "syncytial switch" and propose that the inflammatory milieu that develops during the course of brain abscess may be important for remodeling the types of interactions between resident glia and that deviation from physiological coupling may impact the integrity of brain regions distant from the primary focus of infection. These changes may be dictated by regional variations in Cx expression within the abscess. The objective of the proposed work is to investigate the functional importance of IL-1, TNF-a, and NO in regulating the glial syncytial switch and the role of Cx43 in brain abscess pathogenesis. To address this objective the following Specific Aims will be addressed: (1), to evaluate the consequences of S. aureus and its cell wall product PGN on homocellular GJC in primary astrocytes and microglia and the signaling pathways responsible for the syncytial switch; (2), to establish the functional importance of the proinflammatory mediators IL-1, TNF-a, and NO on modulating glial GJC in response to S. aureus stimulation using primary glia from knockout (KO) mice; and (3), to investigate the role of proinflammatory mediators on connexin expression and the functional importance of Cx43 in disease pathogenesis in a mouse model of S. aureus-induced experimental brain abscess using genetic KO models. Due to the extensive gap junctional coupling of glial cell populations in the normal CNS, neuroinflammatory disruption of normal glial syncytial networks could contribute, in part, to some of the long-term effects observed in patients following brain abscess resolution including seizures and cognitive deficits. These experiments will provide meaningful insights into how proinflammatory mediators influence the extent of glial GJC in brain abscess.
描述(由申请人提供):间隙连接代表接触细胞之间的直接细胞间管道,允许包括离子、代谢前体和第二信使在内的小分子(> 1 kDa)通过。在中枢神经系统(CNS)中广泛的细胞间偶联和大量的缝隙连接的观察表明,一个合胞体样组织的胶质车厢。一种CNS感染性疾病,其中关于其对胶质细胞间隙连接通讯(GJC)的影响一无所知,是化脓性细菌的实质感染,导致脑脓肿的建立。最近的研究表明,在发育中的脑水肿中检测到的由S。金黄色葡萄球菌激活的神经胶质,包括白细胞介素-1(IL-1)、肿瘤坏死因子-α(TNF-α)和一氧化氮(NO)能够调节星形胶质细胞和小神经胶质细胞中的GJC。具体而言,这些分子减弱星形胶质细胞中的GJC,而活化的小胶质细胞在功能上偶联。我们已经创造了这种现象的“合胞体开关”,并提出,在脑脓肿的过程中发展的炎症环境可能是重要的重塑居民胶质细胞之间的相互作用的类型,偏离生理耦合可能会影响远离感染的主要焦点的大脑区域的完整性。这些变化可能取决于脓肿内Cx表达的区域变化。本研究的目的是探讨IL-1、TNF-α和NO在调节胶质细胞合胞体转换中的功能重要性以及Cx43在脑脓肿发病机制中的作用。为了实现这一目标,将致力于以下具体目标:(1),评估S的后果。金黄色葡萄球菌及其细胞壁产物PGN对原代星形胶质细胞和小胶质细胞中同型细胞GJC的影响以及负责合胞体转换的信号通路;(2)确定促炎介质IL-1、TNF-α和NO在调节胶质细胞GJC响应S.金黄色葡萄球菌的小鼠模型中,研究促炎介质对连接蛋白表达的作用和Cx43在疾病发病机制中的功能重要性。使用基因KO模型的金黄色葡萄球菌诱导的实验性脑脓肿。由于正常CNS中胶质细胞群的广泛缝隙连接偶联,正常胶质细胞合胞体网络的神经炎症破坏可能部分导致脑脓肿消退后患者中观察到的一些长期效应,包括癫痫发作和认知缺陷。这些实验将提供有意义的见解如何促炎介质的影响程度的胶质GJC在脑脓肿。

项目成果

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Tammy L Kielian其他文献

Tammy L Kielian的其他文献

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{{ truncateString('Tammy L Kielian', 18)}}的其他基金

Modulating granulocytic myeloid-derived suppressor cell (G-MDSC) metabolic activity to promote Staphylococcus aureus biofilm clearance
调节粒细胞骨髓源性抑制细胞 (G-MDSC) 代谢活性以促进金黄色葡萄球菌生物膜清除
  • 批准号:
    10738662
  • 财政年份:
    2023
  • 资助金额:
    $ 3.14万
  • 项目类别:
T cell-innate immune crosstalk regulates Staphylococcus aureus craniotomy infection
T细胞先天免疫串扰调节金黄色葡萄球菌开颅感染
  • 批准号:
    10590634
  • 财政年份:
    2022
  • 资助金额:
    $ 3.14万
  • 项目类别:
Immune mechanisms that promote S. aureus persistence during craniotomy-associated biofilm infection
开颅手术相关生物膜感染期间促进金黄色葡萄球菌持续存在的免疫机制
  • 批准号:
    9896877
  • 财政年份:
    2018
  • 资助金额:
    $ 3.14万
  • 项目类别:
Immune mechanisms that promote S. aureus persistence during craniotomy-associated biofilm infection
开颅手术相关生物膜感染期间促进金黄色葡萄球菌持续存在的免疫机制
  • 批准号:
    10375439
  • 财政年份:
    2018
  • 资助金额:
    $ 3.14万
  • 项目类别:
Therapeutic targeting of aberrant glial function during Juvenile Batten Disease
幼年巴顿病期间异常神经胶质功能的治疗靶向
  • 批准号:
    8788453
  • 财政年份:
    2014
  • 资助金额:
    $ 3.14万
  • 项目类别:
Therapeutic targeting of aberrant glial function during Juvenile Batten Disease
幼年巴顿病期间异常神经胶质功能的治疗靶向
  • 批准号:
    8660113
  • 财政年份:
    2014
  • 资助金额:
    $ 3.14万
  • 项目类别:
Contribution of extracellular enzymes to Staphylococcus aureus biofilm development
胞外酶对金黄色葡萄球菌生物膜发育的贡献
  • 批准号:
    10665029
  • 财政年份:
    2009
  • 资助金额:
    $ 3.14万
  • 项目类别:
Innate Immunity to S. aureus biofilm
对金黄色葡萄球菌生物膜的先天免疫
  • 批准号:
    7750241
  • 财政年份:
    2009
  • 资助金额:
    $ 3.14万
  • 项目类别:
The Role of Nuclease in Biofilm Development and Disease
核酸酶在生物膜发育和疾病中的作用
  • 批准号:
    7750239
  • 财政年份:
    2009
  • 资助金额:
    $ 3.14万
  • 项目类别:
Innate Immune Response to S. aureus Biofilm
对金黄色葡萄球菌生物膜的先天免疫反应
  • 批准号:
    10665032
  • 财政年份:
    2009
  • 资助金额:
    $ 3.14万
  • 项目类别:

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