Dendritic Cells and Periodontal Disease

树突状细胞和牙周病

• 批准号: 10403515
• 负责人: DANA T GRAVES
• 金额: $ 37.86万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10403515
• 关键词: Ablation; Affect; Alveolar Bone Loss; Antibodies; Antibody Formation; Antibody Response; Award; Bacteria; Bone Resorption; Cell physiology; Cells; Companions; Connective Tissue; Control Groups; Dendritic Cells; Disease susceptibility; Effector Cell; Enterobacteria phage P1 Cre recombinase; Epithelial; Experimental Models; FOXO1A gene; Funding; Fusobacterium nucleatum; Generations; Gingiva; Goals; ITGAX gene; Immune response; Impairment; In Situ Hybridization; In Vitro; Inflammation; LoxP-flanked allele; Lymphocyte Subset; Measures; Mediating; Mus; Oral; Osteoclasts; Pathogenesis; Penetration; Periodontal Diseases; Periodontitis; Play; Porphyromonas gingivalis; Predisposition; Production; Regulatory T-Lymphocyte; Resistance; Role; Th2 Cells; Tissues; Transgenic Mice; Work; adaptive immune response; antibody transfer; bacterial resistance; bone loss; expectation; experimental study; in vivo; insight; lymph nodes; prevent; response; transdifferentiation

Project Summary In the initial funding period of this award we provided conclusive evidence that dendritic cells play a central role in the pathogenesis of periodontal disease and that this function is modulated through FOXO1 and Akt1. Contrary to our expectations, lineage specific FOXO1 deletion in dendritic cells significantly increased susceptibility to periodontitis whereas the opposite result occurred when Akt1 was deleted in dendritic cells. DC-specific Akt1 deletion blocked bacteria-induced periodontitis whereas DC-specific FOXO1 deletion increased it. These exciting results provide the first concrete evidence that DC play an instrumental role in modulating susceptibility to periodontitis and suggest a mechanism through Akt1 and FOXO1. Dendritic cells have multiple functions that can affect periodontal inflammation and bone loss. They may produce factors that may favor the formation of T regs, which have been shown to reduce periodontal breakdown. They also can direct the production of an antibody response that is potentially protective. Alternatively, DCs can transdifferentiate to osteoclasts, effector cells responsible for bone resorption. We will examine each of these three potential mechanisms through which the FOXO1 and Akt1 May regulate DC to control susceptibility to periodontitis. We propose three mechanisms by which FOXO1/Akt1 can modulate susceptibility to periodontitis. These mechanisms are compatible with each other and all three could potentially play a role. The experiments involve an in vivo experimental model of P gingivalis and F nucleatum induced periodontitis in mice with lineage specific FOXO1 or Akt1 deletion in DC along with companion in vitro studies. The goal of Aim 1 is to establish mechanisms through which FOXO1 in dendritic cells modulates periodontal disease susceptibility, while the goal of Aim 2 is to establish mechanisms through which Akt1 has the opposite effect. Three compatible mechanisms will be investigated, modulation of the adaptive immune response by altering Treg/Th2 versus Th1/Th17 responses, alteration of an antibody response that confers protection against periodontal breakdown, and transdifferentiation of immature DC to osteoclasts.

项目概要 在该奖项的初始资助期间，我们提供了确凿的证据，表明树突状细胞发挥着核心作用 其在牙周病发病机制中的作用，并且该功能通过 FOXO1 和 Akt1 进行调节。 与我们的预期相反，树突状细胞中谱系特异性 FOXO1 缺失显着增加 牙周炎的易感性，而当树突状细胞中 Akt1 被删除时，则出现相反的结果。 DC 特异性 Akt1 缺失可阻止细菌诱导的牙周炎，而 DC 特异性 FOXO1 缺失 增加了它。这些令人兴奋的结果提供了第一个具体证据，表明 DC 在 调节牙周炎的易感性并提出通过 Akt1 和 FOXO1 的机制。树突状细胞 具有多种功能，可以影响牙周炎症和骨质流失。它们可能会产生因素 这可能有利于调节性T细胞的形成，而调节性T细胞已被证明可以减少牙周破坏。他们还 可以指导产生潜在保护性的抗体反应。或者，DC 可以 转分化为破骨细胞，即负责骨吸收的效应细胞。我们将逐一检查 FOXO1 和 Akt1 可能通过三种潜在机制调节 DC 来控制对 牙周炎。我们提出了 FOXO1/Akt1 调节敏感性的三种机制 牙周炎。这些机制相互兼容，所有这三种机制都可能发挥作用。 实验涉及牙龈卟啉单胞菌和具核杆菌诱发的牙周炎的体内实验模型 在 DC 中具有谱系特异性 FOXO1 或 Akt1 缺失的小鼠以及伴随的体外研究中。目标 目标 1 是建立树突状细胞中的 FOXO1 调节牙周病的机制 易感性，而目标 2 的目标是建立使 Akt1 产生相反作用的机制。 将研究三种兼容机制，通过改变来调节适应性免疫反应 Treg/Th2 与 Th1/Th17 反应，抗体反应的改变可提供保护 牙周破坏和未成熟 DC 向破骨细胞的转分化。

项目成果

FOXO1 mediates RANKL-induced osteoclast formation and activity.

FOXO1 介导 RANKL 诱导的破骨细胞形成和活性。

• 发表时间: 2015-03-15
• 作者: Wang, Yu;Dong, Guangyu;Jeon, Hyeran Helen;Elazizi, Mohamad;La, Lan B;Hameedaldeen, Alhassan;Xiao, E;Tian, Chen;Alsadun, Sarah;Choi, Yongwon;Graves, Dana T
• 通讯作者: Graves, Dana T

Diabetes mellitus related bone metabolism and periodontal disease.

糖尿病相关骨代谢和牙周病。

• 发表时间: 2015-06-26
• 作者: Wu, Ying;Xiao, E;Graves, Dana T
• 通讯作者: Graves, Dana T

Mechanistic Insight into Orthodontic Tooth Movement Based on Animal Studies: A Critical Review.

基于动物研究的正畸牙齿运动机制洞察：批判性评论。

• 发表时间: 2021-04-16
• 作者: Jeon, Hyeran Helen;Teixeira, Hellen;Tsai, Andrew
• 通讯作者: Tsai, Andrew

Osteoimmunology in Periodontitis and Orthodontic Tooth Movement.

牙周炎和正畸牙齿移动的骨免疫学。

• 发表时间: 2023-04
• 影响因子: 4.3
• 作者: Alghamdi, Bushra;Jeon, Hyeran Helen;Ni, Jia;Qiu, Dongxu;Liu, Alyssia;Hong, Julie J;Ali, Mamoon;Wang, Albert;Troka, Michael;Graves, Dana T
• 通讯作者: Graves, Dana T

Methotrexate promotes recovery of arthritis-induced alveolar bone loss and modifies the composition of the oral-gut microbiota.

甲氨蝶呤促进关节炎引起的牙槽骨损失的恢复并改变口腔肠道微生物群的组成。

• DOI: 10.1016/j.anaerobe.2022.102577
• 发表时间: 2022-04-01
• 期刊: Anaerobe
• 影响因子: 2.3
• 作者: José Alcides Almeida de Arruda;J. D. Corrêa;Y. Singh;S. Oliveira;C. Machado;A. Schneider;J. D. Medeiros;G. Fern;es;es;S. Macari;B. Barrioni;Mariana Avelino de Souza Santos;L. F. Duffles;Helder Takashi Imoto Nakaya;S. Fukada;D. Graves;F. Cunha;T. Silva
• 通讯作者: T. Silva