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: 8093847
• 负责人: Xiaozhe Han
• 金额: $ 29.6万
• 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/8093847
• 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. PUBLIC HEALTH RELEVANCE: An estimated 80% of American adults have some form of periodontal disease, causing oral bone destruction and ultimately leading to tooth loss. The expenditures for treating these conditions far exceed $6 billion/year. Current treatments do not offer complete amelioration of bone loss around teeth because they do not inhibit the biological causes of periodontal bone loss. This application will provide us new knowledge about host immune response in periodontal disease pathogenesis and contribute to development of therapeutic strategies that are effective in preventing tooth loss in people with periodontal disease.

描述（由申请人提供）：牙周炎是由宿主对牙周生物膜中的病原微生物的免疫反应引发的炎性疾病。B淋巴细胞在感染部位密集浸润，并且是NF-：B配体（RANKL）的受体活化剂的主要来源，RANKL是在破骨细胞分化和炎性骨吸收中起关键作用的细胞因子。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（TLR）识别病原体相关分子模式（PAMP），TLR信号传导途径在调节免疫细胞功能中起重要作用，包括细胞因子产生、吞噬作用和程序性细胞死亡（凋亡）。虽然各种B淋巴细胞亚群表达多种TLR，包括TLR 4和TLR 9，但TLR信号传导对B细胞凋亡的作用完全不清楚。本申请的中心假设是TLR 4/TLR 9信号传导的共激活诱导RANKL产生B细胞的凋亡，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，即用TLR 4/9激动剂、LPS和CpG ODN共刺激培养的大鼠脾细胞，增加TLR 4和TLR 9的表达，并增加B细胞凋亡。在本申请中，我们将探索TLR 4/TLR 9信号传导如何使用体外和体内模型调节B细胞凋亡。在特定目标1中，我们将使用体外破骨细胞生成模型确定TLR 4和TLR 9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。在具体目标2中，我们将确定TLR 4/TLR 9的共激活是否诱导B细胞凋亡并减少体内B细胞介导的牙周骨吸收。我们已经开发了一种体内模型的过继B细胞转移/牙龈抗原注射，可用于进行拟议的研究。这项拟议研究的基本原理是，一旦知道TLR信号传导如何控制表达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发生可能是有效的预防牙周炎患者的骨吸收和牙齿脱落。我们还希望，这里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。 公共卫生相关性：据估计，80%的美国成年人患有某种形式的牙周病，导致口腔骨质破坏，最终导致牙齿脱落。治疗这些疾病的费用远远超过60亿美元/年。目前的治疗不能完全改善牙齿周围的骨丢失，因为它们不能抑制牙周骨丢失的生物学原因。这一应用将为我们提供有关牙周病发病机制中宿主免疫反应的新知识，并有助于开发有效预防牙周病患者牙齿脱落的治疗策略。