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）：炎症是伤口愈合的一个关键方面。在牙周病的治疗中，炎症介导的损伤的牙周再生需要干细胞在牙周韧带和牙骨质形成中的活性。该项目考虑的假设是“通过 NF-KB 的炎症信号传导沿成骨细胞谱系调节干细胞分化”。关于间充质干细胞生物学这一方面的信息有限，并且存在令人困惑的可能性，即炎症信号既可以是干细胞植入、规范和分化的正效应器，也可以是负效应器。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，这可能表明改善牙周再生的新目标。实验旨在解决以下具体目标：I) 确定 NF-KB 对间充质干细胞成骨细胞分化的影响； IicB 超级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-KB 对 hMSC 的影响。 II)确定NF-KB对骨诱导信号传导的作用；干细胞样细胞系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 信号传导、b) RUNX2 反式激活和 c) LRP5 信号转导。 Ill) 在骨再生过程中干细胞功能的治疗调节中针对炎症； p6s cre/lox 条件敲除小鼠将被用作 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 超级阻遏物的成骨细胞系和人类 MSC 也将用于研究炎症对骨诱导的影响。建议用炎症原挑战这些模型并用 IKK 抑制剂阻断。表征骨形成细胞对组织修复的炎症信号作用可能会确定治疗牙周炎等慢性炎症性疾病的新治疗靶点和途径。