Post-Transcriptional Regulation of Periodontal Dise

描述(由申请人提供)：牙周病的发生和发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，能与细胞因子mRNAs结合，促进mRNAs的降解。TTP被p38-MK2途径磷酸化，可能是细胞因子mRNA调控的一般机制。这项应用的目的是确定TTP和MK2通路如何改变牙周病的发生和发展。TTP过度表达的牙周炎实验模型显示，促炎蛋白减少，脂多糖诱导的牙槽骨丢失减少。这项建议的初步数据表明，与野生型小鼠相比，缺乏TTP的突变小鼠表现出更多的牙周骨丢失。本研究的目的是1)确定TTP的表达/磷酸化状态在牙周病进展中的作用，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，以及3)检测TTP的表达和磷酸化状态在牙周病进展中的作用。这些研究将确定一种关键的RNA结合蛋白在实验模型和人类牙周炎中的作用。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生物学相关的明确数据。MRNA稳定性的基础和翻译意义将为未来的研究提供洞察力，这些蛋白质将成为改变先天免疫细胞因子表达的潜在靶点，从而在慢性牙周炎的治疗中受益。 公共卫生相关性：牙周病进展是宿主对口腔病原体的免疫炎症反应的结果。这些研究将确定介导炎症细胞因子mRNA稳定性所需的RNA结合蛋白的作用。了解转录后细胞因子调控在牙周炎和骨丢失中的作用的进展可能为牙周病的治疗提供新的可能性。

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. PUBLIC HEALTH RELEVANCE: Periodontal disease progression occurs as a consequence of the host immune inflammatory response to oral pathogens. These studies will establish the role of RNA binding proteins needed to mediate inflammatory cytokine mRNA stability. Progress in understanding the role of posttranscriptional cytokine regulation in periodontal inflammation and bone loss may yield new possibilities for treatment of periodontal diseases.