Post-Transcriptional Regulation of Periodontal Dise

描述（由申请方提供）：牙周病的发生和进展是宿主对口腔病原体的免疫炎症反应的结果。Tristetraprolin（TTP）是一种锌指蛋白，其与细胞因子mRNA的ARE结合并增强mRNA的降解。TTP通过p38-MK2途径被磷酸化，并且可能作为细胞因子mRNA调节的一般机制。本申请的目的是确定TTP和MK2通路如何改变牙周病的发生和进展。TTP过度表达的牙周炎实验模型显示促炎蛋白减少和LPS诱导的牙槽骨丢失量减少。初步数据表明，缺乏TTP的突变小鼠与野生型同窝仔相比，牙周骨丢失量增加。该建议的目的是1）确定TTP表达/磷酸化状态在牙周病进展中指导局部炎性细胞因子表达的作用，2）确定TTP是否将决定牙周病实验模型中炎症和牙槽骨丢失的程度，和3）测量人牙周病进展中的TTP表达和磷酸化状态。这些研究将建立一个关键的RNA结合蛋白在实验模型和人类牙周炎的作用。使用缺乏TTP或调节TTP功能的关键激酶MK2的遗传模型，将获得与牙周病相关的TTP生物学的确切数据。mRNA稳定性的基础和翻译意义将为未来的研究提供这些蛋白质的潜在靶向，这些研究将改变先天免疫细胞因子的表达，从而在慢性牙周炎的管理中获得治疗益处。

DESCRIPTION (provided by applicant): Periodontal disease initiation and progression occurs as a consequence of the host immune inflammatory response to oral pathogens. Tristetraprolin (TTP) is a zinc finger protein that binds to the ARE of cytokine mRNAs and enhances degradation of the mRNA. TTP is phosphorylated by the p38-MK2 pathway and may serve as a general mechanism of cytokine mRNA regulation. The objective of this application is to determine how TTP and the MK2 pathway modify periodontal disease initiation and progression. Experimental models of periodontitis where TTP is over-expressed show a reduction of pro-inflammatory proteins and reduced amount of LPS-induced alveolar bone loss. Preliminary data for this proposal indicates that mutant mice lacking TTP display an increased amount of periodontal bone loss compared with wild type littermates. The aims for this proposal are 1) to determine the role of TTP expression/phosphorylation status directs local inflammatory cytokine expression in periodontal disease progression, 2) to determine if TTP will determine the extent of inflammation and alveolar bone loss in experimental models of periodontal disease, and 3) measure TTP expression and phosphorylation status in human periodontal disease progression. These studies will establish the role of a key RNA binding protein in experimental models and human periodontitis. Using genetic models lacking TTP or the key kinase that modulates TTP function, MK2, definitive data relative to TTP biology related to periodontal disease will be gained. Foundation and translational significance of mRNA stability will provide insight into the potential of these proteins to be targeted for future studies that will modify innate immune cytokine expression for therapeutic benefit in the management of chronic periodontitis.