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

这项研究的目的是了解细胞内源性信号调节的潜在机制 牙周炎的慢性炎症和骨丢失。牙周炎是最常见的炎症性疾病之一 导致牙周组织和牙槽骨破坏的人类疾病，最终 会导致牙齿脱落。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，慢性牙周炎是几种疾病的重要危险因素 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 迫切需要开发新的有效的治疗方法来治疗牙周病。当前 治疗受阻是因为缺乏对细胞内源性正性和 负信号改变会导致牙周组织功能能力的降低，并有助于 牙周病发病率增加。在我们的初步研究中，我们发现Gα13f/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 牙周病损害中的损害。我们还发现了局部Gα13成分活性形式的过表达 (Gα13CA)可减少牙周骨丢失和炎症，修复牙周膜。重要的是，我们 G-α13缺乏通过促进核因子-κB的活化 RhoA下调，AKT活性上调，而腺病毒介导的Gα13过表达可能 有效减轻炎症，减少T细胞和树突状细胞。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性调节因子 Gα13/RhoA/AKT/IKK/NF-κB减轻牙周炎引起的慢性炎症和骨丢失 Gα13信号通路可降低患牙周病的风险。提出了三个具体的测试目标 我们的假设。在目标1中，我们将确定Gα13在巨噬细胞、树突状细胞和OCs中的功能。 牙周炎的牙周炎和牙槽骨丢失的表型和特征 通过功能丧失研究的病理机制。在目标2中，我们将定义Gα13信令在 牙周炎和牙槽骨丢失的表型和发病机制研究 通过功能获得性研究。我们将剖析Gα13信号转导功能的分子机制 G-α-13/RhoA/AKT/IKK/NF-1调控牙周炎及牙周炎的组织和骨丢失 κB途径在巨噬细胞、树突状细胞和OCS中的表达。 深入了解细胞内源性信号调节慢性粒细胞白血病的潜在机制 阐明G-α-13信号转导机制在牙周炎中的作用。 从这项研究中获得的见解可能会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。

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.