Osteoimmunology of Retarded Bone Regeneration in Periodontitis

牙周炎骨再生迟缓的骨免疫学

基本信息

  • 批准号:
    10449982
  • 负责人:
  • 金额:
    $ 35.74万
  • 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:
    2020-08-01 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

Retarded bone regeneration is characteristic to periodontitis. Even after successful conventional periodontal treatment, periodontal bone regeneration rarely, if ever, occurs, while molecular mechanism underlying retarded bone regeneration is largely unknown. This RO1 application proposes to exploit the osteoimmunological roles of osteoclast (OC)-specific cell membrane receptor, Osteoclast Stimulatory Transmembrane Protein (OCSTAMP) and Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) in retarded bone regeneration in periodontitis. During osteoclastic bone resorption, osteoblast (OB)-activation molecules, such as insulin-like growth factor (IGF), act as “coupling” factors released from demineralized bone matrix to ensure that the same amount of bone resorbed by OC is replaced by differentiation and activity of OB. Strong evidence suggests that this coupling mechanism is interrupted (‘uncoupled’) in periodontitis where pathogenic bone resorption exceeds reparative bone formation, resulting in retardation of bone regeneration. Our preliminary results showed that P. gingivalis may be engaged in retarded bone regeneration in periodontitis. A recent study reported that Semaphorin4D (Sema4D) produced by OC inhibits IGF-mediated osteogenesis by OB. The upstream molecular event(s) that induce(s)/upregulate(s) Sema4D expression by RANKL-activated osteoclast precursors (OCp), as well as the mechanism of Sema4D action on OB in the context of periodontitis, are unknown. We preliminary identify the ligand for OCSTAMP is produced by activated OCp, and the binding of this ligand with OCSTAMP elicits signals for Sema4D-expression. Furthermore, periodontal pathogen, P. gingivalis, appears to upregulate the Sema4D production from OCp by upregulating the generation of OCSTAMP ligand. Based on these preliminary findings and published evidence, we hypothesized that pathogenic activation of OCSTAMP by its ligand upregulate the production of Sema4D form OCp which, in turn, inhibits osteogenesis in periodontitis. To test our hypothesis, the following two Specific Aims are proposed. Aim 1: To elucidate the molecular mechanism underlying the generation of ligand for OC-STAMP, Aim 2: To assess the impact of OC-STAMP-activation on retarded bone regeneration in a mouse model of periodontitis induced by the combination of ligature attachment and P. gingivalis infection. This study will, for the first time, elucidate the pathologic osteoimmunological mechanism that interrupts new bone formation in alveolar bone affected by periodontitis, thus, representing a potential paradigm shift in the development of novel periodontitis therapies.
骨再生迟缓是牙周炎的特征。即使在成功的传统牙周 治疗,牙周骨再生很少,如果有的话,发生,而分子机制的基础 骨再生迟缓在很大程度上是未知的。此RO 1应用程序建议利用 破骨细胞(OC)特异性细胞膜受体,破骨细胞刺激因子 树突状细胞特异性跨膜蛋白(DC-STAMP) 延缓牙周炎中的骨再生。在骨吸收过程中,成骨细胞(OB)活化 分子,如胰岛素样生长因子(IGF),作为“耦合”因子从脱矿骨释放 基质,以确保相同数量的骨吸收OC被替换的分化和活性, OB.强有力的证据表明,这种耦合机制在牙周炎中被中断(“非耦合”), 致病性骨吸收超过修复性骨形成,导致骨再生的延迟。 我们的初步结果表明,牙龈卟啉单胞菌可能参与延缓骨再生, 牙周炎最近的一项研究报道,OC产生的Semaphorin 4D(Sema 4D)抑制IGF介导的 OB成骨。诱导/上调Sema 4D表达的上游分子事件, RANKL激活的破骨细胞前体(OCp),以及Sema 4D对OB的作用机制, 牙周炎的背景,是未知的。我们初步确定OCSTAMP的配体是由 活化的OCp,并且该配体与OCSTAMP的结合释放了Sema 4D表达的信号。 此外,牙周病原体牙龈卟啉单胞菌似乎通过以下途径上调OCp的Sema 4D产生: 上调OCSTAMP配体的产生。根据这些初步调查结果和公布的证据, 我们假设OCSTAMP通过其配体的致病性激活上调Sema 4D的产生, 形成OCp,OCp反过来抑制牙周炎中的骨生成。为了验证我们的假设,以下两个 提出了具体目标。目的1:阐明配体产生的分子机制 对于OC-STAMP,目的2:评估OC-STAMP激活对骨再生延迟的影响, 结扎附着和牙龈卟啉单胞菌感染联合诱导的小鼠牙周炎模型。 这项研究将首次阐明阻断新骨形成的病理性骨免疫机制。 因此,牙周炎影响牙槽骨的骨形成,代表了牙周病研究中潜在的范式转变。 开发新型牙周炎治疗方法。

项目成果

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TOSHIHISA KAWAI其他文献

TOSHIHISA KAWAI的其他文献

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{{ truncateString('TOSHIHISA KAWAI', 18)}}的其他基金

Osteoimmunology of Retarded Bone Regeneration in Periodontitis
牙周炎骨再生迟缓的骨免疫学
  • 批准号:
    10451355
  • 财政年份:
    2021
  • 资助金额:
    $ 35.74万
  • 项目类别:
Osteoimmunology of Retarded Bone Regeneration in Periodontitis
牙周炎骨再生迟缓的骨免疫学
  • 批准号:
    10451354
  • 财政年份:
    2021
  • 资助金额:
    $ 35.74万
  • 项目类别:
Osteoimmunology of Retarded Bone Regeneration in Periodontitis
牙周炎骨再生迟缓的骨免疫学
  • 批准号:
    10667111
  • 财政年份:
    2020
  • 资助金额:
    $ 35.74万
  • 项目类别:
POC Biosensor for Periodontitis
用于牙周炎的 POC 生物传感器
  • 批准号:
    9905270
  • 财政年份:
    2020
  • 资助金额:
    $ 35.74万
  • 项目类别:
Role of OC-STAMP expressed on human osteoclasts in periodontitis
人破骨细胞上表达的 OC-STAMP 在牙周炎中的作用
  • 批准号:
    10792429
  • 财政年份:
    2020
  • 资助金额:
    $ 35.74万
  • 项目类别:
Role of platelets in periodontal bone remodeling.
血小板在牙周骨重塑中的作用。
  • 批准号:
    10087691
  • 财政年份:
    2020
  • 资助金额:
    $ 35.74万
  • 项目类别:
Osteoimmunology of Retarded Bone Regeneration in Periodontitis
牙周炎骨再生迟缓的骨免疫学
  • 批准号:
    10219233
  • 财政年份:
    2020
  • 资助金额:
    $ 35.74万
  • 项目类别:
Osteoimmunology of Retarded Bone Regeneration in Periodontitis
牙周炎骨再生迟缓的骨免疫学
  • 批准号:
    10885237
  • 财政年份:
    2020
  • 资助金额:
    $ 35.74万
  • 项目类别:
POC Biosensor for Periodontitis
用于牙周炎的 POC 生物传感器
  • 批准号:
    10244668
  • 财政年份:
    2020
  • 资助金额:
    $ 35.74万
  • 项目类别:
POC Biosensor for Periodontitis
用于牙周炎的 POC 生物传感器
  • 批准号:
    10177999
  • 财政年份:
    2020
  • 资助金额:
    $ 35.74万
  • 项目类别:
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