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 先天免疫在牙周病发病中的作用特别是 将利用P-和E-选择素缺陷小鼠（P/E（-/-））的新模型来 研究先天免疫的作用，特别是Toll样受体 (TLR)牙周病的治疗。先前的研究表明，P/E（-/-）小鼠 患上一种进行性牙周炎，这种牙周炎在牙齿脱落后不久就开始了。 出疹，其特征是口腔植物群质量增加， 致病性，牙龈炎症，骨表达增加 再吸收细胞因子IL-1和广泛的骨丢失。此外，抗生素 治疗可完全防止骨质流失。有人建议，这种模式提供 与其他系统相比的优点，包括天然存在的性质， 疾病，牙周破坏的速度，控制和 操纵口腔植物群和宿主免疫反应，以及 大量的试剂和基因工程菌株调查人员 将测试牙周破坏可以通过以下方式改善的假设： 调节TLR、它们的信号传导途径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测序来表征口腔植物群， P/E（-/-）、P/E（+/+）和抗生素处理的小鼠; 2）测定免疫抑制剂对小鼠免疫功能的影响。 在P/E（-/-）小鼠中病原体激活的机制。细胞浸润，细胞因子 和Toll样受体（TLR）将在体内和体外表征; 3） 确定TLRs在细胞因子和共刺激分子中的作用 对病原体的反应。TLR信号的显性负性结构 转导分子将被用于抑制TLR应答， 确定病原体诱导的细胞因子应答。此外，TLR在 将评估免疫应答向Th1和Th2分布的偏移; 4） 探讨TLRs和细胞因子在牙周骨破坏中的作用。 将使用敲除小鼠和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。这些长期目标 研究的目的是确定先天免疫在牙周炎中的作用， 将这些信息应用于免疫调节剂的开发， 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.