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。在牙周病的治疗中，炎症介导的牙周损伤的再生需要干细胞在骨牙周膜和牙骨质的形成中发挥活性。本项目中考虑的假设是“通过NF-κ B的炎症信号传导调节干细胞沿着成骨细胞谱系的分化”。关于间充质干细胞生物学的这一方面，只有有限的信息是可用的，并且存在混淆的可能性，即炎症信号可以是干细胞植入、特化和分化的正效应子和负效应子。我们的长期目标是确定间充质干细胞对NF-κ B介导的炎症刺激的反应，这可能是改善牙周再生的新靶点。提出实验以解决以下具体目标：I）确定NF-κ B对间充质干细胞成骨细胞分化的作用; IicB超阻遏物将用于调节细胞功能，IKK的药理学抑制剂将用于确定NF-κ B对hMSC的作用。II）确定NF-κ B对骨诱导信号传导的作用;将使用干细胞样和成骨细胞系的瞬时转染来确定炎性刺激如何影响a）Smad信号传导、B）RUNX 2反式激活和c）LRP 5信号转导。III）在骨再生期间干细胞功能的治疗性调节中靶向炎症; p6 s cre/lox条件性敲除小鼠将用作NF-κ B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期间的作用。表达NF-κ B或IKB超阻遏物的成骨细胞系和人MSC也将用于研究炎症对骨诱导的影响。提出了用炎性因子阻断这些模型并用IKK抑制剂阻断。表征用于组织修复的骨形成细胞的出现的炎症信号传导效应可以确定用于治疗慢性炎症性疾病如牙周炎的新的治疗靶点和途径。