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
• 负责人: YI-PING LI
• 金额: $ 36.1万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404267
• 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.

本研究的目的是了解细胞内源性信号如何调节 慢性炎症和骨质流失的年龄相关性牙周炎。牙周炎是最常见的一种 导致牙周组织和牙槽骨破坏的人类炎性疾病， 最终导致牙齿脱落，特别是在老年人群中，并可能表现为全身性疾病。 由于低反应率和副作用，目前的治疗方法不能有效地解决牙周病。 在人口老龄化中，这是一个重大挑战。然而，这种作用背后的机制 G α 13在炎症性疾病，包括牙周病，特别是在生理老化和 病理性牙周炎，以及G α 13调节牙周的分子机制 炎症仍然未知。目前的治疗受到缺乏了解的机制， 生理变化如何导致牙周组织的年龄相关性减少 牙周病是牙周病的一种常见类型。在初步研究中， 发现G α 13）的表达随着小鼠年龄的增加而显著降低，我们揭示， Gna13f/fLysM-Cre小鼠表现出严重的骨丢失，OC数量显著增加， 牙周病病变。我们还发现， 在牙周炎诱导的模型中Gna13缺乏，而局部Gna13组成性活性过表达 形式（Gna13CA）导致牙周骨丢失和炎症减少，并修复PDL。基于 在我们的初步研究中，我们假设G α 13是一个主要的负调节因子， 牙周炎通过G α 13/RhoA/AKT/IKK/NF-κ B通路诱导慢性炎症和骨丢失， G α 13激活和信号传导增加可降低年龄相关性牙周病的风险。三个具体 目的是为了检验我们的假设。在目的1中，我们将确定G α 13缺陷在 单核细胞对加重牙周炎症和牙骨质、牙周膜（PDL）和牙槽骨 通过表征条件性基因敲除小鼠模型的表型和病理机制， 衰老相关性牙周炎。目的2：明确单核细胞中G α 13在减弱单核细胞增殖中的作用， 牙周炎症和牙周膜，牙骨质和牙槽骨的损失，通过表征 Gna13 OE转基因小鼠模型的表型和病理机制及AAV介导的G α 13局部表达 在老化相关性牙周炎中的过度表达。我们将剖析G α 13 调节牙周炎症和牙周组织和骨丢失在年龄相关性牙周炎，通过 G α 13/RhoA/AKT/IKK/NF-κ B和整合素信号通路。这项研究将提供重要的 老年牙周炎骨吸收和炎症的负调节 阐明G α 13信号转导的潜在机制。