Regulation of B-Cell Apoptosis by TLR Signaling in Periodontal Disease

牙周病中 TLR 信号转导对 B 细胞凋亡的调节

• 批准号: 8270446
• 负责人: Xiaozhe Han
• 金额: $ 24.66万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270446
• 关键词: Activated B-Lymphocyte; Adoptive Transfer; Adult; Agonist; Alveolar Bone Loss; American; Animal Model; Antigens; Apoptosis; B-Lymphocyte Subsets; B-Lymphocytes; Biological; Biological Assay; Bone Resorption; Cell Culture System; Cell physiology; Cells; Clinical Microbiology; Coculture Techniques; Detection; Disease; Environment; Expenditure; Gene Expression; Gingiva; Goals; Immune; Immune response; Immunology; In Vitro; Induction of Apoptosis; Infection; Inflammatory; Injection of therapeutic agent; Knowledge; Learning; Ligands; Link; Measurement; Mediating; Microbial Biofilms; Modeling; Molecular; Natural Immunity; Oral; Osteoclasts; Pathogenesis; Pathway interactions; Pattern; Periodontal Diseases; Periodontitis; Phagocytosis; Play; Preventive; Production; Proteins; RNA; Rattus; Receptor Signaling; Regulation; Research; Research Personnel; Resource Sharing; Resources; Role; Signal Pathway; Signal Transduction; Site; Source; Splenocyte; System; TLR4 gene; TNFSF11 gene; Testing; Therapeutic; Toll-like receptors; Tooth Loss; Tooth structure; Transgenic Mice; Work; adaptive immunity; arm; base; bone; bone loss; cytokine; gain of function; in vivo; in vivo Model; inflammatory bone resorption; innovation; loss of function; microorganism; novel therapeutics; osteoclastogenesis; pathogen; prevent; receptor; response; therapeutic development

DESCRIPTION (provided by applicant): Periodontitis is an inflammatory disease triggered by host immune response to pathogenic microorganisms in the periodontal biofilm. B lymphocytes are densely infiltrated at the site of infection and are a primary source of receptor activator of NF-:B ligand (RANKL), a cytokine that plays a pivotal role in osteoclast differentiation and inflammatory bone resorption. Our long-term goal is to determine the molecular mechanisms which control immune cell-mediated periodontal bone resorption in periodontitis for preventive and therapeutic purposes. Toll-like receptors (TLRs) recognize pathogen associated molecular patterns (PAMPs) and TLR signaling pathways play an important role in regulating immune cell functions, including cytokine production, phagocytosis, and programmed cell death (apoptosis). While various B lymphocyte subsets express multiple TLRs, including TLR4 and TLR9, the role of TLR signaling on B cell apoptosis is entirely unclear. The central hypothesis of this application is that co-activation of TLR4/TLR9 signaling induces apoptosis of RANKL-producing B cells, thus diminishing B cell-mediated periodontal bone resorption. Our hypothesis is based on our preliminary results demonstrating that co-stimulation with TLR4/9 agonists, LPS and CpG ODN, elevated expressions of TLR4 and TLR9 and increased B cell apoptosis in cultured rat splenocytes. In this application we will explore how TLR4/TLR9 signaling regulates B cell apoptosis using both in vitro and in vivo models. In Specific Aim 1, we will determine if co-activation of TLR4 and TLR9 induce RANKL-expressing B cell apoptosis, thereby inhibiting B cell-mediated osteoclastogenesis, using an in vitro osteoclastogenesis model. In Specific Aim 2, we will determine whether co-activation of TLR4/TLR9 induces B cell apoptosis and decreases B cell-mediated periodontal bone resorption in vivo. We have developed an in vivo model of adoptive B cell transfer/gingival antigen injection that can be used to undertake the proposed research. The rationale for the proposed research is that, once it is known how TLR signaling controls RANKL-expressing B cell apoptosis, therapeutic strategies based on induction of RANKL-expressing B cell apoptosis, therefore, inhibition of B cell-mediated osteoclastogenesis may be effective in preventing bone resorption and tooth loss in people with periodontitis. It is also expected that what is learned here could be applicable to the understanding of other immune-mediated bone-resorptive disorders.

描述（由申请人提供）：牙周炎是由宿主对牙周生物膜中病原微生物的免疫反应引发的炎症性疾病。B淋巴细胞在感染部位密集浸润，是NF-:B配体受体激活剂（RANKL）的主要来源，RANKL是一种细胞因子，在破骨细胞分化和炎症性骨吸收中起关键作用。我们的长期目标是确定控制免疫细胞介导的牙周骨吸收的分子机制，以预防和治疗牙周炎。toll样受体（TLRs）识别病原体相关分子模式（PAMPs）和TLR信号通路在调节免疫细胞功能，包括细胞因子产生、吞噬和程序性细胞死亡（凋亡）中发挥重要作用。虽然多种B淋巴细胞亚群表达多种TLR，包括TLR4和TLR9，但TLR信号在B细胞凋亡中的作用尚不清楚。本应用的中心假设是TLR4/TLR9信号的共同激活诱导产生rankl的B细胞凋亡，从而减少B细胞介导的牙周骨吸收。我们的假设是基于我们的初步结果，表明TLR4/9激动剂、LPS和CpG ODN共同刺激培养的大鼠脾细胞，升高TLR4和TLR9的表达，增加B细胞凋亡。在这个应用中，我们将探索TLR4/TLR9信号如何通过体外和体内模型调节B细胞凋亡。在Specific Aim 1中，我们将使用体外破骨细胞生成模型，确定TLR4和TLR9的共激活是否诱导表达rankl的B细胞凋亡，从而抑制B细胞介导的破骨细胞生成。在Specific Aim 2中，我们将在体内确定TLR4/TLR9的共激活是否会诱导B细胞凋亡并减少B细胞介导的牙周骨吸收。我们已经开发了一种过继性B细胞转移/牙龈抗原注射的体内模型，可以用于进行拟议的研究。这项研究的基本原理是，一旦了解了TLR信号如何控制表达rankl的B细胞凋亡，基于诱导表达rankl的B细胞凋亡的治疗策略，因此，抑制B细胞介导的破骨细胞生成可能有效地防止牙周炎患者的骨吸收和牙齿脱落。我们也期望在此学到的东西可以适用于其他免疫介导的骨吸收疾病的理解。