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
• 负责人: YI-PING LI
• 金额: $ 34.91万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444932
• 关键词: Activities of Daily Living; Age; Aging; Alveolar Bone Loss; Attenuated; Bacteria; Bone Resorption; Cells; Chronic; Dental Cementum; Dental Plaque; Dependovirus; Disease; Exhibits; Foundations; Genes; Goals; Guanine; Hemostatic function; Human; Immune response; Incidence; Inflammation; Inflammatory; Integrin Signaling Pathway; Lesion; Macrophage Activation; Mediating; Modeling; Molecular; Mus; NF-kappa B; Oral health; Osteitis; Osteoclasts; Osteolytic; Pathologic; Pathway interactions; Periodontal Diseases; Periodontal Ligament; Periodontitis; Phenotype; Physiological; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Risk; Role; Signal Pathway; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Tissues; Tooth Loss; Tooth structure; Transgenic Mice; aged; aging population; alveolar bone; base; bone; bone loss; conditional knockout; design; gain of function; insight; ligament injury; macrophage; monocyte; mouse model; novel; novel therapeutic intervention; overexpression; repaired; response; sex; side effect

The goal of this study is to understand the mechanisms underlying how cell endogenous signaling regulates chronic inflammation and bone loss in aging-associated 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 results in teeth loss, especially in aged population, and potentially manifests into systemic conditions. Periodontal disease is inefficiently tackled by current therapeutics due to low response rates and adverse side effects presenting a significant challenge in the aging population. However, the mechanism underlying the role of Gα13 in inflammation diseases, including periodontal disease, especially under physiological aging and pathological periodontitis, as well as the molecular mechanism by which Gα13 regulates periodontal inflammation remains unknown. Current therapy is hindered by lack of understanding of the mechanisms underlying how physiological changes result in an age-associated reduction of periodontal tissues tissue functional capacity and contribute to increased incidence of periodontal disease. In our preliminary studies we found that the expression of Gα13) significantly decreases as mice age increases, and we revealed that Gna13f/fLysM-Cre mice exhibited severe bone loss with a significant increase in OC number, and PDL damage in periodontal disease lesions. We also found exacerbated alveolar bone loss and PDL damage associated with Gna13 deficiency in a periodontitis-induced model, while overexpression of local Gna13 constitutively active form (Gna13CA) resulted in reduced periodontal bone loss and inflammation and repaired PDL. Based on our preliminary studies, we hypothesize that Gα13 is a master negative regulator that inhibits periodontitis-induced chronic inflammation and bone loss through Gα13/RhoA/AKT/IKK/NF-κB pathway and the increased Gα13 activate and signaling reduce the risk for age-associated periodontal disease. Three specific aims are proposed to test our hypothesis. In Aim 1, we will determine the function of Gα13 deficiency in monocytes on exacerbating periodontal inflammation and cementum, periodontal ligament (PDL), and alveolar bone loss by characterizing the phenotypes and pathomechanism of conditional knockout mouse models in aging-associated periodontitis. In Aim 2, we will define the function of Gα13 in monocytes on attenuating periodontal inflammation and periodontal ligament, cementum, and alveolar bone loss by characterizing the phenotypes and pathomechanism of Gna13OE transgenic mouse models and AAV mediated Gα13 local overexpression in aging-associated periodontitis. We will dissect the molecular mechanism by which Gα13 regulates periodontal inflammation and periodontal tissue and bone loss in age-associated periodontitis through Gα13/RhoA/AKT/IKK/NF-κB, and integrins signaling pathways. The proposed study will provide important insights into the negative regulation of bone resorption and inflammation in aged-associated periodontitis by elucidating the underlying mechanism of Gα13 signaling.

这项研究的目的是了解细胞内源信号如何调节细胞的基础机制 衰老相关牙周炎的慢性炎症和骨质流失。牙周炎是最常见的 人类的炎症性疾病会导致牙周组织和牙槽骨的破坏，这 最终导致牙齿流失，尤其是在老年人口中，并可能体现在系统性状态。 由于反应率低和不良方面，当前疗法对牙周疾病效率低下 影响在老龄化人群中带来重大挑战。但是，发挥作用的机制 炎症疾病中的Gα13，包括牙周疾病，尤其是在身体衰老和 病理牙周炎以及Gα13调节牙周炎的分子机制 炎症仍然未知。由于缺乏对机制的理解而阻碍了当前的疗法 基本的身体变化如何导致年龄相关的牙周组织减少 功能能力并有助于增加牙周疾病的发生率。在我们的初步研究中 发现Gα13的表达随着小鼠的年龄增长而显着降低，我们透露 GNA13F/FLYSM-CRE小鼠暴露了严重的骨质流失，OC数量显着增加，而PDL损坏 牙周疾病病变。我们还发现与 牙周炎诱导的模型中的GNA13缺乏症，而局部GNA13的过表达组成性活性 形式（GNA13CA）导致牙周骨质流失和注射减少，并修复了PDL。基于 我们的初步研究，我们假设Gα13是抑制的主负调节剂 牙周炎引起的慢性感染和通过Gα13/rhoa/akt/ikk/ikk/nf-κB途径和骨质流失 Gα13激活和信号传导的增加降低了与年龄相关的牙周疾病的风险。三个具体 提出了目的来检验我们的假设。在AIM 1中，我们将确定Gα13缺陷的功能 加重牙周感染和牙骨质，牙周韧带（PDL）和肺泡的单核细胞 通过表征有条件基因敲除小鼠模型的表型和病理机制来骨丢失 衰老相关的牙周炎。在AIM 2中，我们将定义单核细胞中Gα13的功能 通过表征 GNA13OE转基因小鼠模型和AAV介导的Gα13局部的表型和病理机理 衰老相关牙周炎的过表达。我们将剖析Gα13的分子机制 通过调节牙周感染和牙周组织和与年龄相关的牙周炎的骨骼损失 Gα13/rhoA/akt/ikk/nf-κB和整联蛋白信号通路。拟议的研究将提供重要的 洞察骨骼分辨率和炎症的负调控，通过老年相关牙周炎 阐明Gα13信号传导的基本机制。