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

通过靶向细胞内源性负信号传导抑制牙周病中的炎症和骨侵蚀

• 批准号: 10405318
• 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: 2021-05-14 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405318
• 关键词: Activities of Daily Living; Adult; Age; Alveolar Bone Loss; Arthritis; Atherosclerosis; Attenuated; Bone Resorption; Cardiovascular Diseases; Cells; Chronic; Dendritic Cells; Dependovirus; Diabetes Mellitus; Disease; Dominant-Negative Mutation; Exhibits; Foundations; Goals; Guanine; Human; Immune; In Vitro; Incidence; Inflammation; Inflammatory; Lead; Lesion; Mediating; Molecular; Mus; NF-kappa B; Osteitis; Osteoclasts; Osteolytic; Pathologic; Pathway interactions; Periodontal Diseases; Periodontal Ligament; Periodontitis; Phenotype; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; System; T-Lymphocyte; Testing; Therapeutic; Tissues; Tooth Loss; alveolar bone; base; bone erosion; bone loss; design; gain of function; in vivo; insight; ligament injury; loss of function; macrophage; novel; novel therapeutic intervention; overexpression; repaired; response; side effect

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.

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 牙周炎的慢性炎症和骨质流失。牙周炎是最常见的炎症之一 人类的疾病导致牙周组织和牙槽骨的破坏，最终 导致牙齿脱落。据估计，大多数30岁以上的成年人都患有牙周骨质流失。 此外，越来越多的证据表明，慢性牙周感染是多个的重要危险因素 病理疾病，包括心血管疾病，糖尿病，动脉粥样硬化和关节炎。因此，有 迫切需要开发新颖有效的治疗方法来治疗牙周疾病。当前的 缺乏对细胞内源性阳性和 负信号传导变化导致牙周组织功能的降低，并有助于 牙周疾病的增加。在我们的初步研究中，我们发现Gα13F/flysm-cre小鼠 暴露于严重的骨质流失，OC数量显着增加，并标记为牙周韧带（PDL） 牙周疾病病变的损害。我们还发现局部Gα13组成型活性形式的过表达 （Gα13CA）导致牙周骨质流失和感染减少，并修复了PDL。重要的是，我们 证明Gα13缺乏通过 下调的RhoA并更新了AKT活动，并且AAV介导的Gα13过表达可以 通过改善T细胞和树突状细胞有效减少炎症。基于我们的初步研究 我们假设巨噬细胞，树突状细胞和破骨细胞的内源性负调节剂 通过Gα13/rhoa/akt/ikk/ikk/nf-κB减弱牙周炎诱导的慢性感染和骨质流失 途径和Gα13信号传导降低了牙周疾病的风险。提出了三个特定目标来测试 我们的假设。在AIM 1中，我们将确定Gα13在巨噬细胞，树突细胞和OC中的功能 通过表征表型和 通过功能丧失研究来致病机理。在AIM 2中，我们将定义Gα13信号的功能 牙周炎症和肺泡骨质流失通过表征表型和病理机制 通过功能收益研究。我们将剖析Gα13信号传导函数的分子机制 通过Gα13/rhoa/akt/ikk/ikk/nf-调节牙周感染和组织和骨质流失 巨噬细胞，树突状细胞和AIM 3中的κB途径。拟议的研究将提供重要的研究 了解细胞内源信号如何调节慢性的机制的洞察力 通过阐明Gα13信号传导的潜在机制，牙周炎的炎症和骨质流失。 从这项研究中获得的见解可能为促进新颖设计的最终目标提供了基础 牙周和骨质疾病的治疗方法。