Inflammatory Control of Periodontal Regeneration

牙周再生的炎症控制

• 批准号: 7489507
• 负责人: LYNDON F COOPER
• 金额: $ 34.45万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7489507
• 关键词: Address; Affect; Bone Regeneration; Cell Differentiation process; Cell Line; Cell physiology; Cells; Cellular biology; Cementoblast; Chondroblast; Chronic; Clinical; Data; Dental Cementum; Disease; Engraftment; Fibroblasts; Flow Cytometry; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Healed; Human Cell Line; I-kappa B Proteins; In Vitro; Inflammation; Inflammatory; Knock-out; Knockout Mice; Lesion; Mediating; Mesenchymal Stem Cells; Microbe; Modeling; Myoblasts; Natural regeneration; Oral; Osteoblasts; Osteogenesis; Particulate; Pathway interactions; Periodontal Diseases; Periodontal Ligament; Periodontitis; Periodontium; Process; Range; Research Personnel; Role; Signal Transduction; Source; Stem cells; Stimulus; Testing; Therapeutic; Transactivation; Transfection; Work; Wound Healing; base; bone; healing; improved; inhibitor/antagonist; mouse model; novel therapeutics; programs; research study; response; stem; success; therapeutic target; tissue regeneration

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.

描述（由申请人提供）：炎症是伤口愈合的关键方面。在治疗牙周疾病时，炎症介导的损伤的牙周再生需要干细胞活性在骨牙周韧带和牙骨质的形成中。该项目中考虑的假设是“通过NF-KB进行的炎症信号传导调节沿成骨细胞谱系的干细胞分化”。只有有关间充质干细胞生物学这一方面的有限信息，并且有可能的是，炎症信号可能是干细胞植入，规范和分化的正面和负面效应子。我们定义间充质干细胞对NF-KB介导的炎症性刺激的远距离目标可能表明改善牙周再生的新目标。提出了实验来解决以下特定目的：i）定义NF-KB对间充质干细胞成骨细胞分化的影响； IICB超级压迫器将用于调节细胞功能，IKK的药理抑制剂将用于确定NF-KB对HMSC的影响。 ii）确定NF-KB在骨诱导信号传导中的作用；茎状和成骨细胞系的瞬时转染将用于定义炎症刺激如何影响a）SMAD信号传导，b）Runx2反式激活和C）LRP5信号转导。生病的）靶向炎症在骨骼再生过程中干细胞功能的治疗调节中； P6S CRE/LOX条件基因敲除小鼠将用作NF-KB缺陷细胞的来源，以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超级压迫剂的成骨细胞系和人类MSC也将用于研究对骨诱导的炎症影响。提出了用炎症剂和IKK抑制剂阻塞来挑战这些模型。出现骨形成细胞对组织修复的炎症信号传导作用的表征可以确定新的治疗靶标和途径，以治疗慢性炎性疾病（如牙周炎）。