Inhibiting inflammation and bone erosion in periodontal disease by targeting cell endogenous negative signaling

通过靶向细胞内源性负信号传导抑制牙周病中的炎症和骨侵蚀

基本信息

  • 批准号:
    10559645
  • 负责人:
  • 金额:
    $ 35.03万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-05-14 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

The goal of this study is to understand the mechanisms underlying how cell endogenous signaling regulates chronic inflammation and bone loss in periodontitis. Periodontitis is one of the most common inflammatory diseases in humans that results in the destruction of periodontal tissues and alveolar bone, which ultimately lead to teeth loss. It is estimated that majority of adults over the age of 30 suffer from periodontal bone loss. Also, growing evidence suggests that chronic periodontal inflammation is an important risk factor for several pathological disorders including cardiovascular disease, diabetes, atherosclerosis and arthritis. Hence, there is an urgent need to develop novel and efficient therapeutic approaches to treat periodontal disease. Current therapy is hindered by lack of understanding of the mechanisms underlying how cell endogenous positive and negative signaling changes result in the reduction of periodontal tissues functional capacity and contribute to increased incidence of periodontal disease. In our preliminary studies, we found that Gα13f/fLysM-Cre mice exhibited severe bone loss with a significant increase in OC number, and marked periodontal ligament (PDL) damage in periodontal disease lesions. We also found overexpression of local Gα13 constitutively active form (Gα13CA) resulted in reduced periodontal bone loss and inflammation and repaired PDL. Importantly, we demonstrated that Gα13 deficiency promoted nuclear factor kappa B (NF-κB) activation through downregulated RhoA and upregulated AKT activity, and that AAV-mediated Gα13 overexpression could effectively reduce inflammation with decreased T cells and dendritic cells. Based on our preliminary studies, we hypothesize that Endogenous negative regulators of macrophages, dendritic cells and osteoclasts attenuates periodontitis-induced chronic inflammation and bone loss through the Gα13/RhoA/AKT/IKK/NF-κB pathway, and Gα13 signaling reduces the risk for periodontal disease. Three specific aims are proposed to test our hypothesis. In Aim 1, we will determine the function of Gα13 in macrophages, dendritic cells, and OCs in periodontal inflammation and alveolar bone loss in periodontitis by characterizing the phenotypes and pathomechanism through loss-of-function studies. In Aim 2, we will define the function of Gα13 signaling on periodontal inflammation and alveolar bone loss by characterizing the phenotypes and pathomechanism through gain-of-function studies. We will dissect the molecular mechanism of the Gα13 signaling function in regulating periodontal inflammation and tissue and bone loss in periodontitis through Gα13/RhoA/AKT/IKK/NF- κB pathway in macrophages, dendritic cells, and OCs in Aim 3. The proposed study will provide important insights into understand the mechanisms underlying how cell endogenous signaling regulates chronic inflammation and bone loss in periodontitis by elucidating the underlying mechanism of Gα13 signaling. Insights gained from this study may provide foundation for the ultimate goal of facilitating the design of novel therapeutic approach for periodontal and osteolytic diseases.
本研究的目的是了解细胞内源性信号如何调节 牙周炎的慢性炎症和骨质流失。牙周炎是最常见的炎症之一, 牙周病是人类的一种疾病,它导致牙周组织和牙槽骨的破坏, 导致牙齿脱落。据估计,大多数30岁以上的成年人患有牙周骨丢失。 此外,越来越多的证据表明,慢性牙周炎是一个重要的危险因素, 病理性疾病包括心血管疾病、糖尿病、动脉粥样硬化和关节炎。因此,有 迫切需要开发新的和有效的治疗方法来治疗牙周病。电流 由于缺乏对细胞内源性阳性和阴性细胞如何在体内表达的机制的理解, 负信号的变化导致牙周组织功能能力的降低, 牙周病的发病率增加。在我们的初步研究中,我们发现Gα 13 f/fLysM-Cre小鼠 表现出严重的骨丢失,OC数量显著增加,牙周膜(PDL)明显 牙周病的危害。我们还发现了局部Gα13组成型活性形式的过度表达, (Gα 13 CA)导致牙周骨丢失和炎症减少,并修复PDL。重要的是我们 表明Gα13缺陷通过以下途径促进核因子κ B(NF-κB)活化: AAV介导的Gα13过表达下调RhoA,上调AKT活性, 通过减少T细胞和树突状细胞有效地减轻炎症。根据我们的初步研究, 我们假设巨噬细胞、树突状细胞和破骨细胞的内源性负调节因子 通过Gα13/RhoA/AKT/IKK/NF-κB减轻牙周炎诱导的慢性炎症和骨丢失 Gα13信号通路可降低牙周病的风险。提出了三个具体目标来测试 我们的假设在目的1中,我们将确定Gα13在巨噬细胞、树突状细胞和OC中的功能。 牙周炎中的牙周炎症和牙槽骨丢失, 病理机制通过功能丧失的研究。在目标2中,我们将定义Gα13信号转导在 牙周炎和牙槽骨丢失的表型和病理机制的特点 通过功能获得研究。我们将剖析Gα13信号功能的分子机制, Gα13/RhoA/AKT/IKK/NF-κ B对牙周炎炎症及组织和骨丢失的调控作用 Aim 3中巨噬细胞、树突状细胞和OC中的κB通路。这项研究将提供重要的 深入了解细胞内源性信号如何调节慢性炎症的机制 通过阐明Gα13信号转导的潜在机制来研究牙周炎中的炎症和骨丢失。 从本研究中获得的启示可以为促进小说设计的最终目标提供基础 牙周和溶骨性疾病的治疗方法。

项目成果

期刊论文数量(24)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Odanacatib, A Cathepsin K-Specific Inhibitor, Inhibits Inflammation and Bone Loss Caused by Periodontal Diseases.
  • DOI:
    10.1902/jop.2015.140643
  • 发表时间:
    2015-08
  • 期刊:
  • 影响因子:
    4.3
  • 作者:
    Hao L;Chen J;Zhu Z;Reddy MS;Mountz JD;Chen W;Li YP
  • 通讯作者:
    Li YP
C/ebpα controls osteoclast terminal differentiation, activation, function, and postnatal bone homeostasis through direct regulation of Nfatc1.
  • DOI:
    10.1002/path.5001
  • 发表时间:
    2018-03
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Chen W;Zhu G;Tang J;Zhou HD;Li YP
  • 通讯作者:
    Li YP
TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease.
  • DOI:
    10.1038/boneres.2016.9
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    12.7
  • 作者:
    Wu M;Chen G;Li YP
  • 通讯作者:
    Li YP
Silencing of atp6v1c1 prevents breast cancer growth and bone metastasis.
RNAi-mediated silencing of Atp6i and Atp6i haploinsufficiency prevents both bone loss and inflammation in a mouse model of periodontal disease.
  • DOI:
    10.1371/journal.pone.0058599
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Jiang H;Chen W;Zhu G;Zhang L;Tucker B;Hao L;Feng S;Ci H;Ma J;Wang L;Stashenko P;Li YP
  • 通讯作者:
    Li YP
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YI-PING LI其他文献

YI-PING LI的其他文献

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{{ truncateString('YI-PING LI', 18)}}的其他基金

G13 signaling attenuates periodontal inflammation and alveolar bone loss in the mouse model of age-associated periodontitis
G13 信号传导可减轻年龄相关性牙周炎小鼠模型中的牙周炎症和牙槽骨丢失
  • 批准号:
    10404267
  • 财政年份:
    2021
  • 资助金额:
    $ 35.03万
  • 项目类别:
Inhibiting inflammation and bone erosion in periodontal disease by targeting cell endogenous negative signaling
通过靶向细胞内源性负信号传导抑制牙周病中的炎症和骨侵蚀
  • 批准号:
    10405318
  • 财政年份:
    2021
  • 资助金额:
    $ 35.03万
  • 项目类别:
Mechanism of chemotherapy potentiation of muscle wasting in cancer cachexia
化疗增强癌症恶病质肌肉萎缩的机制
  • 批准号:
    10362568
  • 财政年份:
    2021
  • 资助金额:
    $ 35.03万
  • 项目类别:
G13 signaling attenuates periodontal inflammation and alveolar bone loss in the mouse model of age-associated periodontitis
G13 信号传导可减轻年龄相关性牙周炎小鼠模型中的牙周炎症和牙槽骨丢失
  • 批准号:
    10444932
  • 财政年份:
    2021
  • 资助金额:
    $ 35.03万
  • 项目类别:
Inhibiting inflammation and bone erosion in periodontal disease by targeting cell endogenous negative signaling
通过靶向细胞内源性负信号传导抑制牙周病中的炎症和骨侵蚀
  • 批准号:
    10327686
  • 财政年份:
    2021
  • 资助金额:
    $ 35.03万
  • 项目类别:
Mechanism of chemotherapy potentiation of muscle wasting in cancer cachexia
化疗增强癌症恶病质肌肉萎缩的机制
  • 批准号:
    10550259
  • 财政年份:
    2021
  • 资助金额:
    $ 35.03万
  • 项目类别:
Targeting circulating HSP70 and HSP90 for the treatment of cancer cachexia
靶向循环 HSP70 和 HSP90 治疗癌症恶病质
  • 批准号:
    10212970
  • 财政年份:
    2020
  • 资助金额:
    $ 35.03万
  • 项目类别:
Characterizing the negative signaling in dendritic cells and macrophages to attenuate inflammation and bone destruction in rheumatoid arthritis
表征树突状细胞和巨噬细胞中的负信号传导以减轻类风湿性关节炎的炎症和骨质破坏
  • 批准号:
    10616608
  • 财政年份:
    2020
  • 资助金额:
    $ 35.03万
  • 项目类别:
Characterizing the negative signaling in dendritic cells and macrophages to attenuate inflammation and bone destruction in rheumatoid arthritis
表征树突状细胞和巨噬细胞中的负信号传导以减轻类风湿性关节炎的炎症和骨质破坏
  • 批准号:
    10405848
  • 财政年份:
    2020
  • 资助金额:
    $ 35.03万
  • 项目类别:
Characterizing the negative signaling in dendritic cells and macrophages to attenuate inflammation and bone destruction in rheumatoid arthritis
表征树突状细胞和巨噬细胞中的负信号传导以减轻类风湿性关节炎的炎症和骨质破坏
  • 批准号:
    10321665
  • 财政年份:
    2020
  • 资助金额:
    $ 35.03万
  • 项目类别:

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