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

基本信息

批准号：
10327686
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
项目类别：
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/10327686
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

项目摘要

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.

本研究的目的是了解细胞内源信号如何调节的机制牙周炎的慢性炎症和骨质流失是最常见的炎症之一。导致牙周组织和牙槽骨破坏的人类疾病，最终导致牙周组织和牙槽骨的破坏。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，慢性牙周炎症是多种疾病的重要危险因素。病理疾病包括心血管疾病、糖尿病、动脉粥样硬化和关节炎。当前迫切需要开发新颖且有效的治疗方法来治疗牙周病。由于缺乏对细胞内源性阳性和潜在机制的了解，治疗受到阻碍。负信号变化导致牙周组织功能能力降低，并导致在我们的初步研究中，我们发现 Gα13f/fLysM-Cre 小鼠牙周病的发病率增加。表现出严重的骨质流失，OC 数量显着增加，牙周膜 (PDL) 明显我们还发现局部 Gα13 组成型活性形式的过度表达。 (Gα13CA) 导致牙周骨质流失和炎症减少，并修复 PDL。证明 Gα13 缺陷通过以下方式促进核因子 kappa B (NF-κB) 激活下调 RhoA 并上调 AKT 活性，AAV 介导的 Gα13 过表达可以根据我们的初步研究，通过减少 T 细胞和树突状细胞来有效减轻炎症，我们追求巨噬细胞、树突状细胞和破骨细胞的内源性负调节因子通过 Gα13/RhoA/AKT/IKK/NF-κB 减轻牙周炎引起的慢性炎症和骨质流失通路，Gα13 信号传导降低了牙周病的风险，提出了三个具体的测试目标。在我们的假设中，我们将确定 Gα13 在巨噬细胞、树突状细胞和 OC 中的功能。通过表征表型和牙周炎中的牙周炎症和牙槽骨丢失在目标 2 中，我们将定义 Gα13 信号传导的功能。通过表征表型和病理机制来研究牙周炎症和牙槽骨丢失通过功能获得研究，我们将剖析 Gα13 信号传导功能的分子机制。通过 Gα13/RhoA/AKT/IKK/NF- 调节牙周炎症以及牙周炎中的组织和骨丢失目标 3 中巨噬细胞、树突状细胞和 OC 中的 κB 通路。拟议的研究将提供重要的信息深入了解细胞内源信号如何调节慢性病的潜在机制通过阐明 Gα13 信号传导的潜在机制来研究牙周炎中的炎症和骨质流失。从这项研究中获得的见解可以为促进小说设计的最终目标提供基础牙周病和溶骨性疾病的治疗方法。