权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of sphingosine-1-phosphate receptor 2 in the pathogenesis of periodontitis

1-磷酸鞘氨醇受体2在牙周炎发病机制中的作用

基本信息

批准号：
9004621
负责人：
Hong Yu
金额：
$ 11.21万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9004621
关键词：
Adult Affect Alveolar Bone Loss Animal Model Animals Atherosclerosis Attenuated Bacteria Binding Bone Marrow Bone Marrow Cells Cell membrane Cells Chemotaxis Conditioned Culture Media Cre-LoxP Dinoprostone Disease Foundations G-Protein-Coupled Receptors Generations Goals Homeostasis Immune response In Vitro Infiltration Inflammatory Interleukin-1 beta Interleukin-6 Knockout Mice Leukocytes Lipids Macrophage Colony-Stimulating Factor Malignant Neoplasms Mammalian Cell Mediating Mus Oral Osteoblasts Osteoclasts Osteoporosis PTGS2 gene Pathogenesis Periodontitis Physiological Process Production Protein Kinase RNA Interference Research Rheumatoid Arthritis Rho-associated kinase Role SPHK1 enzyme Signal Pathway Signal Transduction Signaling Molecule Sphingosine-1-Phosphate Receptor System TLR4 gene TNF gene TNFSF11 gene Testing Tissues Tooth Loss United States bone bone loss cytokine eIF-2 Kinase in vivo inflammatory bone loss mRNA Expression macrophage migration monocyte new therapeutic target novel novel therapeutic intervention novel therapeutics oral pathogen osteoclastogenesis pathogen public health relevance research study response rho sphingosine 1-phosphate

项目摘要

DESCRIPTION (provided by applicant): Periodontitis is a bacteria-driven inflammatory bone loss disease affecting 47% of adults in the United States. Oral pathogens, such as Aggregatibacter actinomycetemcomitans (Aa), the pathogen associated with localized aggressive periodontitis, stimulate mammalian cells to generate and release sphingosine-1-phosphate (S1P). S1P binds to five G protein-coupled receptors, which initiates various cellular signaling pathways and affects many physiological and pathophysiological processes. However, it is unknown how S1P signaling modulates the inflammatory bone loss response induced by oral pathogens. The long-term goal is to understand the role of S1P signaling in regulating the immune response to oral pathogens and to develop a novel therapeutic strategy for periodontitis. Our preliminary study demonstrated that S1P signaling is critical in regulating the immune response to Aa. In a periodontal inflammatory bone loss animal model, deficiency in generation of S1P in mice (sphingosine kinase 1 KO mice) attenuated periodontal leukocyte infiltration and alleviated alveolar bone loss in response to Aa stimulation. Additionally, pharmacological inhibition or RNA silencing of S1P receptor 2 (S1PR2) in murine bone marrow-derived macrophages (BMM) significantly attenuated COX-2, IL-1ß, IL-6, and TNF mRNA expressions induced by Aa. Furthermore, pharmacological inhibition of S1PR2 in BM-derived preosteoclasts suppressed osteoclastogenesis induced by Aa-stimulated conditioned media. The overall objective of this application is to establish S1PR2-mediated signaling as a key modulator in regulating the immune response to the oral pathogen Aa. We hypothesize that the Aa-induced proinflammatory bone loss response is mediated through S1PR2 signaling. Blocking S1PR2 signaling will reduce proinflammatory cytokine production, attenuate osteoclastogenesis, and alleviate alveolar bone loss induced by Aa. We will test these two specific aims to determine if 1) S1PR2 deficiency in vitro will significantly decrease ERK, PLC, Rho, and NF-ĸB protein kinase activities, reduce proinflammatory cytokine production, and attenuate osteoclastogenesis in response to Aa exposure. Additionally, we will determine if blocking S1PR2 will decrease osteoclastogenic factors RANK, RANKL, and M-CSF. 2) S1PR2 deficiency in vivo will decrease periodontal leukocyte infiltration, alleviate proinflammatory cytokine production, and attenuate alveolar bone loss. Under the first aim, we will use BMM or preosteoclasts derived from S1pr2+/+ and S1pr2-/- mice to determine if S1PR2 deficiency in cells will reduce the immune response to Aa. Additionally, we will determine if blocking S1PR2 will decrease RANK, RANKL, and M-CSF induced by Aa in BMM or osteoblasts. Under the second aim, we will use an Aa-induced periodontal inflammatory bone loss animal model to determine if S1PR2 deficiency in mice will reduce the inflammatory bone loss response induced by Aa. This study will elucidate the role of S1PR2 signaling, a novel key mechanism, in the pathogenesis of periodontitis. This study will define a new therapeutic target and lay the foundation to develop a novel therapeutic strategy for periodontitis by targeting S1PR2.