INNATE IMMUNITY AND PERIODONTAL DISEASE IN MICE

描述：这是一个修改后的应用程序，用于研究元素的作用 先天免疫在牙周病发病机制中的作用具体地说，一个 新的P-和E-选择素缺陷小鼠模型(P/E(-/-))将被用于 研究先天免疫的作用，特别是Toll样受体 (TLR)，在牙周病中。先前的研究表明，P/E(-/-)小鼠 发生在牙齿后不久的进行性牙周炎 出疹，其特征是口腔菌群质量增加和 致病性、牙周炎、骨骼表达增加 吸收细胞因子IL-1和广泛的骨丢失。此外，抗生素 治疗可以完全防止骨质流失。有人建议这种模式提供 相对于其他系统的优势，包括自然发生的 疾病，牙周破坏的速度，控制和控制的能力 控制口腔菌群和宿主的免疫反应，以及 大量的试剂和基因工程菌株。调查人员 将检验牙周破坏可以通过以下方法改善的假设 调节TLR，它们的信号通路，以及它们诱导的细胞因子。 拟议的研究分为四个具体目标：1)确定 导致P/E(-/-)小鼠疾病的牙周病原体；这些 研究将利用16S rRNA测序来表征口腔菌群 P/E(-/-)、P/E(/)和抗生素处理的小鼠；2)测定免疫 病原体对P/E(-/-)小鼠的激活机制。细胞浸润，细胞因子 以及Toll样受体(TLRs)的体内和体外特征；3) TLRs在细胞因子和共刺激分子中的功能测定 对病原体做出反应的表达。TLR信号的显性否定结构 转导分子将被用来抑制TLR反应，并对 病原体诱导的细胞因子反应测定。此外，TLRs在以下方面的作用 将评估免疫反应偏向Th1和Th2的情况；4) 探讨TLRs和细胞因子在牙周骨破坏中的作用。 将利用基因敲除小鼠和IL-1、IL-6和IL-10的调节来建立 这些因素在牙周骨丢失中的作用。这些项目的长期目标是 研究目的是确定先天免疫在牙周炎中的作用，并 将这些信息应用于免疫调节剂的开发，以改善 疾病。

DESCRIPTION: This is a revised application to study the role of elements of innate immunity in the pathogenesis of periodontal disease. Specifically, a novel model of P- and E-selectin deficient mice (P/E(-/-)) will be utilized to investigate the role of innate immunity, specifically, Toll-like receptors (TLR), in periodontal disease. Previous studies have shown that P/E(-/-) mice develop a progressive periodontitis that is initiated shortly after tooth eruption, and is characterized by an oral flora that is increased in mass and pathogenicity, gingival inflammation, increased expression of the bone resorptive cytokine IL-1, and extensive bone loss. Moreover, antibiotic treatment completely prevents bone loss. It is suggested that this model offers advantages over other systems, including the naturally occurring nature of the disease, the rapidity of periodontal destruction, the ability to control and manipulate the oral flora and the host immune response, and the availability of a vast array of reagents and genetically-engineered strains. The investigators will test the hypothesis that periodontal destruction can be ameliorated by modulating TLRs, their signaling pathways, and the cytokines that they induce. The proposed study is divided into four Specific Aims: 1) to identify the periodontal pathogens that are responsible for disease in P/E(-/-) mice; these studies will utilize 16S rRNA sequencing to characterize the oral flora in P/E(-/-), P/E(+/+) , and antibiotic treated mice; 2) to determine the immune mechanisms activated by pathogens in P/E(-/-) mice. Cell infiltrates, cytokines and Toll-like receptors (TLRs) will be characterized in vivo and in vitro; 3) to determine the function of TLRs in cytokine and co-stimulatory molecule expression in response to pathogens. Dominant negative constructs of TLR signal transducing molecules will be used to inhibit TLR responses and the effect on pathogen-induced cytokine responses determined. Also, the role of TLRs in skewing the immune response towards a Th1 and Th2 profile will be assessed; 4) to determine the roles of TLRs and cytokines in periodontal bone destruction. Knockout mice and modulation of IL-1, IL-6 and IL-10 will be used to establish the role of these factors in periodontal bone loss. The long-term goal of these studies is to determine the role of innate immunity in periodontitis and to apply this information to the development of immune modulators that ameliorate disease.