Inflammatory Control of Periodontal Regeneration

描述（由申请人提供）：炎症是伤口愈合的一个关键方面。在牙周病的治疗中，炎症介导损伤的牙周再生需要在牙周韧带和骨质形成中的干细胞活性。本项目考虑的假设是“炎症信号通过NF-KB调节干细胞沿成骨细胞谱系分化”。关于间充质干细胞生物学这方面的信息有限，炎症信号可能是干细胞植入、分化和分化的积极和消极影响因素，这一可能性令人困惑。我们的长期目标是确定间充质干细胞对nf - kb介导的炎症刺激的反应，这可能为改善牙周再生指明新的目标。我们提出了以下具体的实验目的：1)确定NF-KB对间充质干细胞成骨分化的影响；IicB超抑制因子将用于调节细胞功能，IKK的药理学抑制剂将用于确定NF-KB对hMSCs的影响。II)确定NF-KB在成骨诱导信号传导中的作用；干细胞样细胞和成骨细胞系的瞬时转染将用于确定炎症刺激如何影响a) Smad信号，b) RUNX2转激活和c) LRP5信号转导。ii)在骨再生过程中靶向炎症治疗性调节干细胞功能；我们将利用p6s cre/lox条件敲除小鼠作为NF-KB缺陷细胞的来源，研究其在异位骨形成模型中观察到的干细胞植入和分化过程中的作用。表达NF-KB或IKB超抑制因子的成骨细胞系和人间充质干细胞也将用于研究炎症对骨诱导的影响。提出用炎症因子和IKK抑制剂阻断这些模型。表征组织修复中骨形成细胞出现的炎症信号效应可能为牙周炎等慢性炎症性疾病的治疗找到新的治疗靶点和途径。

DESCRIPTION (provided by applicant): Inflammation is a key aspect of wound healing. In treatment of periodontal disease, periodontal regeneration of inflammation-mediated damage requires stem cell activity in the formation of bone periodontal ligament and cementum. The hypothesis considered in this project is that "inflammatory signaling through NF-KB modulates stem cell differentiation along the osteoblastic lineage". Only limited information is available regarding this aspect of mesenchymal stem cell biology, and there is the confounding possibility that inflammatory signals can be both positive and negative effectors of stem cell engraftment, specification and differentiation. Our long range goal of defining mesenchymal stem cell responses to NF-KB-mediated inflammatory stimuli may indicate new targets for improving periodontal regeneration. Experiments are proposed to address the following specific aims: I) to define the effect of NF-KB on mesenchymal stem cell osteoblastic differentiation; IicB super-repressor will be used to modulate cell function and pharmacologic inhibitors of IKK will be used to determine NF-KB effects on hMSCs. II) to determine the role of NF-KB on osteoinductive signaling; transient transfection of stem-like and osteoblastic cell lines will be used to define how inflammatory stimuli affect a) Smad signaling, b) RUNX2 transactivation and c) LRP5 signal transduction. Ill) to target inflammation in the therapeutic modulation of stem cell function during bone regeneration; a p6s cre/lox conditional knockout mouse will be used as a source of NF-KB deficient cells to study its role during stem cell engraftment and differentiation observed in ectopic bone formation models. Osteoblastic cell lines and human MSCs expressing NF-KB or IKB super-repressor will also be used to study inflammation effects on osteoinduction. Challenging these models with inflammatory agens and blocking with IKK inhibitors is proposed. Characterization of inflammatory signaling effects of the emergence bone forming cells for tissue repair may identify new therapeutic targets and avenues for treatment of chronic inflammatory diseases like periodontitis.