G13 signaling attenuates periodontal inflammation and alveolar bone loss in the mouse model of age-associated periodontitis

这项研究的目的是了解细胞内源性信号调节的潜在机制 老年性牙周炎的慢性炎症和骨丢失。牙周炎是最常见的 人类的炎症性疾病，导致牙周组织和牙槽骨的破坏， 最终导致牙齿脱落，特别是在老年人口中，并可能表现为全身疾病。 由于有效率低和副作用大，目前的治疗方法对牙周病的治疗效果不佳。 对老龄化人口构成重大挑战的影响。然而，潜在的作用机制是 Gα13在炎症疾病中的作用，包括牙周病，特别是在生理性衰老和 病理性牙周炎以及G-α13调节牙周的分子机制 炎症仍不清楚。目前的治疗由于缺乏对机制的了解而受到阻碍。 生理变化如何导致与年龄相关的牙周组织减少 功能能力，并导致牙周病发病率增加。在初步研究中，我们 我们发现，随着小鼠年龄的增长，G-α的表达显著降低。 GNa13f/fLysM-CRE小鼠表现出严重的骨质丢失，OC数量显著增加，PDL损伤 牙周病病变。我们还发现，加剧的牙槽骨丢失和牙周韧带损伤与 在牙周炎诱导的模型中Gna 13缺乏，而局部Gna 13的过度表达具有结构性活性 Form(Gna 13CA)可减少牙周骨丢失和炎症，修复牙周膜。基于 我们的初步研究，我们假设Gα13是一个主要的负调控因子，它抑制了 G-α13/RhoA/AKT/IKK/NF-κB途径诱导牙周炎慢性炎症和骨丢失 G-α13的激活和信号转导增加可降低患年龄相关性牙周病的风险。三个具体的 提出的目的是为了检验我们的假设。在目标1中，我们将确定Gα13缺乏在 单核细胞加重牙周炎与牙骨质、牙周膜和牙槽骨的关系 条件基因敲除小鼠模型的表型和发病机制研究 年龄相关性牙周炎。在目标2中，我们将定义单核细胞中Gα13在减毒中的作用 牙周炎与牙周膜、牙骨质和牙槽骨丢失 腺病毒介导的G-α-13基因转基因小鼠模型的表型和致病机制 衰老相关牙周炎中的过度表达。我们将剖析Gα13的分子机制 通过以下途径调节年龄相关性牙周炎的牙周炎、牙周组织和骨丢失 Gα13/RhoA/akt/ikk/nf-κB和整合素信号转导通路。拟议的研究将提供重要的 老年牙周炎对骨吸收和炎症的负性调节作用 阐明G-α-13信号转导机制。

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.