Innate Immune Bacterial Recognition and Osteoclastogenesis

先天免疫细菌识别和破骨细胞生成

基本信息

  • 批准号:
    7556643
  • 负责人:
  • 金额:
    $ 46.91万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-07-20 至 2011-06-30
  • 项目状态:
    已结题

项目摘要

A. Specific Aims* Periodontal disease is a well-characterized chronic inflammatory bone destructive disease induced by bacterial infection with the Gram-negative pathogen Porphyromonas gingivalis. The cellular composition of inflammatory bone lesions in human periodontal disease consists of T and B cells, macrophages and dendritic cells (69,82,93). In other inflammatory bone diseases these cells have been reported to contribute to the acceleration of bone resorption by the production of proinflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and receptor activator of nuclear factor κB ligand (RANKL) (54,94,104). In addition, macrophages contribute to bone resorption through their differentiation to osteoclasts (1). Osteoclasts play an important role in bone resorption and in vitro studies have established that osteoclast differentiation occurs through RANKL and proinflammatory cytokine dependent mechanisms (8,61,71). However the ability of infectious agents to stimulate osteoclast differentiation is not well defined (56). P. gingivalis induces the production of an array of proinflammatory cytokines in various host cells in vitro (45,125). We recently reported that P. gingivalis infected macrophages induce osteoclastogenesis in vitro by a TNF-α dependent / RANKL-independent mechanism which was dependent on the innate immune receptor Toll-like receptor, TLR2 (118). We also reported that TLR2 but not TLR4, was crucial for P. gingivalis induced oral inflammatory bone loss in a mouse model (45). Additional studies have established that B and T cells and proinflammatory cytokines contribute to oral inflammatory bone loss in response to P. gingivalis (15,41,45). Despite these observations, the role of TNF-α and RANKL in P. gingivalis mediated inflammatory oral bone loss in vivo is not known. In this project we will test the hypothesis that specific TLR2 responsive immune cells produce proinflammatory cytokines in response to infection with P. gingivalis, which contribute to inflammatory oral bone loss in vivo. The following Aims are proposed: Aim 1. To define the role of TNF-α and RANKL in P. gingivalis-induced oral inflammatory bone loss in a mouse model. A. We will examine P. gingivalis induced inflammatory bone loss in C57BL/6 and TNFR-/- mice. We will examine what immune cells constitute the inflammatory lesion induced following P. gingivalis infection and the innate immune signaling receptors and cytokines (TNF-α and RANKL) expressed by these cells. B. We will examine the contribution of RANKL to P. gingivalis induced oral bone loss using OPG in P. gingivalis infected C57BL/6 and TNFR-/- mice. Aim 2. To define which TLR2 responding immune cells contribute to P. gingivalis-induced oral inflammatory bone loss in a mouse model. We will define which immune cells contribute to the TLR2 signaling response induced following P. gingivalis challenge by performing adoptive transfer studies with macrophages in C57BL/6 and TLR2-/- mice. We propose that an interplay between host specific immune cells and their responses to P. gingivalis plays a critical role in chronic inflammatory bone loss induced by P. gingivalis. Our studies will define the role of TLR2 responsive immune cells in inflammatory bone loss in vivo following stimulation with P. gingivalis. Enhanced understanding of the roles of specific immune cells and pathways that participate in proinflammatory cytokine expression and osteoclastogenesis in response to bacterial infection will provide a promising avenue for novel therapies for chronic inflammatory bone disorders. *References numbers are found in the “Literature Cited” section of the original grant application.
A.具体目标 * 牙周病是一种慢性炎症性骨质破坏性疾病 由革兰氏阴性病原体牙龈卟啉单胞菌的细菌感染引起。的 人牙周炎性骨损害的细胞组成由T和B组成 细胞、巨噬细胞和树突状细胞(69、82、93)。在其他炎症性骨病中,这些细胞 据报道,通过产生 促炎细胞因子,包括肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β、IL-6和 核因子κB配体受体激活剂(RANKL)(54,94,104)。此外,巨噬细胞 通过分化为破骨细胞促进骨吸收(1)。破骨细胞发挥着 在骨吸收中重要作用,体外研究已经证实破骨细胞分化 通过RANKL和促炎细胞因子依赖性机制发生(8、61、71)。然而 感染因子刺激破骨细胞分化的能力还不明确(56)。 P.牙龈炎可诱导多种宿主产生一系列促炎细胞因子 体外细胞(45,125)。我们最近报道牙龈卟啉单胞菌感染的巨噬细胞诱导 通过TNF-α依赖性/RANKL非依赖性机制体外破骨细胞生成, 依赖于先天免疫受体Toll样受体TLR 2(118)。我们还报道了TLR 2 而不是TLR 4,对于牙龈卟啉单胞菌诱导的小鼠模型中的口腔炎性骨丢失至关重要(45)。 另外的研究已经证实,B和T细胞以及促炎细胞因子有助于 牙龈卟啉单胞菌引起的口腔炎性骨质流失(15,41,45)。尽管有这些意见, TNF-α和RANKL在体内牙龈卟啉单胞菌介导的炎性口腔骨丢失中的作用尚不清楚。 在这个项目中,我们将测试特定的TLR 2应答免疫细胞产生的假设, 促炎细胞因子响应于牙龈卟啉单胞菌感染,其有助于炎症性 体内口腔骨丢失。建议的目标如下: 目标1。探讨TNF-α和RANKL在牙龈卟啉单胞菌诱导的口腔炎性骨形成中的作用 小鼠模型中的损失。A.我们将研究牙龈卟啉单胞菌诱导的炎症性骨丢失, C57 BL/6和TNFR-/-小鼠。我们将检查哪些免疫细胞构成炎性病变 诱导的牙龈卟啉单胞菌感染和先天免疫信号受体和细胞因子 (TNF-α和RANKL)。B。我们将研究RANKL对P的贡献。 在牙龈卟啉单胞菌感染的C57 BL/6和TNFR-/-小鼠中使用OPG观察牙龈卟啉单胞菌诱导的口腔骨丢失。 目标2.为了确定哪些TLR 2应答免疫细胞有助于牙龈卟啉单胞菌诱导的口腔免疫, 在小鼠模型中的炎性骨丢失。我们将确定哪些免疫细胞有助于 通过进行过继转移诱导牙龈卟啉单胞菌攻击后的TLR 2信号转导应答 在C57 BL/6和TLR 2-/-小鼠中使用巨噬细胞的研究。 我们认为宿主特异性免疫细胞和它们对P. 牙龈卟啉单胞菌在牙龈卟啉单胞菌诱导的慢性炎性骨丢失中起关键作用。我们的研究 将定义TLR 2应答性免疫细胞在体内炎性骨丢失中的作用, 刺激牙龈卟啉单胞菌。增强对特定免疫细胞作用的理解, 参与促炎细胞因子表达和破骨细胞生成的途径 将为慢性炎症性骨的新疗法提供一个有希望的途径 紊乱 * 参考文献编号可在原始资助申请的“引用文献”部分找到。

项目成果

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Caroline A Genco其他文献

Caroline A Genco的其他文献

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{{ truncateString('Caroline A Genco', 18)}}的其他基金

Porphyromonas gingivalis and Pancreatic Carcinogenesis in Mouse Models
小鼠模型中牙龈卟啉单胞菌与胰腺癌发生
  • 批准号:
    9519194
  • 财政年份:
    2018
  • 资助金额:
    $ 46.91万
  • 项目类别:
Microbial Disruption of Dendritic Cell Maturation and Function
树突状细胞成熟和功能的微生物破坏
  • 批准号:
    10237941
  • 财政年份:
    2018
  • 资助金额:
    $ 46.91万
  • 项目类别:
Microbial Disruption of Dendritic Cell Maturation and Function
树突状细胞成熟和功能的微生物破坏
  • 批准号:
    10468732
  • 财政年份:
    2018
  • 资助金额:
    $ 46.91万
  • 项目类别:
Microbial Disruption of Dendritic Cell Maturation and Function
树突状细胞成熟和功能的微生物破坏
  • 批准号:
    9790936
  • 财政年份:
    2018
  • 资助金额:
    $ 46.91万
  • 项目类别:
The Gonococcal Fur Regulon Link to Pathogenesis
淋球菌毛皮调节子与发病机制的联系
  • 批准号:
    9751634
  • 财政年份:
    2017
  • 资助金额:
    $ 46.91万
  • 项目类别:
Global Transcriptome Analysis of Mucosal Gonoccal Infection
粘膜淋菌感染的全局转录组分析
  • 批准号:
    9333190
  • 财政年份:
    2016
  • 资助金额:
    $ 46.91万
  • 项目类别:
TLR4 evasion, bacterial persistence and chronic inflammation
TLR4 逃避、细菌持续存在和慢性炎症
  • 批准号:
    8926492
  • 财政年份:
    2014
  • 资助金额:
    $ 46.91万
  • 项目类别:
TLR4 evasion, bacterial persistence and chronic inflammation
TLR4 逃避、细菌持续存在和慢性炎症
  • 批准号:
    9117800
  • 财政年份:
    2014
  • 资助金额:
    $ 46.91万
  • 项目类别:
Global transcriptome analysis of mucosal gonococcal infection
粘膜淋球菌感染的全局转录组分析
  • 批准号:
    9101453
  • 财政年份:
    2014
  • 资助金额:
    $ 46.91万
  • 项目类别:
Global transcriptome analysis of mucosal gonococcal infection
粘膜淋球菌感染的全局转录组分析
  • 批准号:
    8889364
  • 财政年份:
    2014
  • 资助金额:
    $ 46.91万
  • 项目类别:

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