GAS6-Mediated Regulation of Oral Tissue Regeneration

GAS6 介导的口腔组织再生调节

• 批准号: 10032927
• 负责人: Ann Marie Decker
• 金额: $ 13.93万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-10 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10032927
• 关键词: Address; Alveolar; Apoptotic; Award; Biology; Bone Marrow; Bone Regeneration; Bone Tissue; Bone Transplantation; Cells; Data; Defect; Dental; Differentiation and Growth; Disease; Epithelial; Epithelium; Esthetics; Future; Generations; Genetic; Goals; Growth; Hematopoietic; Immune; Immunology; Impairment; Inflammation; Inflammatory; Injury; Lead; Measurement; Mediating; Mesenchymal; Mesenchymal Stem Cells; Modeling; Monitor; Morphology; Mus; Natural regeneration; Neutrophil Infiltration; Neutrophilic Infiltrate; Oral; Oral cavity; Osteoblasts; Pathway interactions; Patients; Phenotype; Physiological; Physiology; Positioning Attribute; Process; Production; Quality of life; Regulation; Resolution; Role; Scientist; Signal Transduction; Source; Techniques; Testing; Therapeutic; Tissues; Tooth Loss; Training; Trauma; Traumatic injury; Work; alveolar bone; base; bone; career; cohort; conditional knockout; edentulism; experimental study; extracellular; healing; loss of function; macrophage; mouse model; neutrophil; novel; novel therapeutic intervention; novel therapeutics; oral tissue; regenerative; repaired; side effect; soft tissue; standard of care; targeted treatment; thrombogenesis; tissue regeneration; tool; wound closure; wound healing

Project Summary Tooth loss from trauma or disease remains a significant world-wide concern due to poor esthetics and loss of function. Addressing this issue is not trivial because regeneration of alveolar bone and oral tissue is not predictable, partially due to the complexity of the process. Bone regeneration of these defects remains unpredictable and understanding the physiological mechanisms that guide bone marrow biology and inflammatory resolution will increase the therapeutic reliability of these regenerative techniques in the future. We have observed a previously unknown role for Growth Arrest Specific 6 (GAS6) in controlling alveolar bone and soft tissue regeneration following extraction. GAS6-deficient mice showed markedly worse healing following extraction, which was associated with aberrant bone and immune phenotypes. The primary goal for this K99/R00 proposal is to test the critical role of GAS6 in oral tissue healing. Two specific aims are proposed based on our previous observations. We hypothesize that GAS6 acts directly on mesenchymal stem cells to prime them towards a osteoblastic phenotype. This hypothesis will be tested through measurement of healing following extraction in mice with mesenchymal stem cells deficient in GAS6 signaling, along with associated experiments on primary cells derived from patients following extraction. We also hypothesize that increased neutrophil infiltrate in GAS6-deificiency impedes soft tissue healing. We will employ conditional knockout models of neutrophils and neutrophil functions to test this hypothesis. The K99 portion will be dedicated to developing new tools for studying tissue and immune cell-specific GAS6 signaling and building upon my prior work in osteoblast biology, while the R00 portion will deploy these tools to study inflammation and connect alveolar regeneration with GAS6 signaling. This award will provide a significant contribution to the understanding of the physiology of healing in the oral cavity while providing significant training to the candidate in the use of genetic mouse models and immunology, ultimately leading to an independent career as a dental clinician-scientist specializing in treatment of systemically compromised patients.

项目概要 由于美观性差和牙齿缺失，外伤或疾病造成的牙齿缺失仍然是全世界关注的一个重大问题。 功能。解决这个问题并非易事，因为牙槽骨和口腔组织的再生并非易事。 可以预见，部分原因是过程的复杂性。这些缺陷的骨再生仍然存在 不可预测并了解指导骨髓生物学的生理机制 炎症消退将提高未来这些再生技术的治疗可靠性。 我们观察到生长停滞特异性 6 (GAS6) 在控制牙槽骨方面发挥着以前未知的作用 以及拔牙后的软组织再生。 GAS6缺陷小鼠的愈合能力明显较差 拔牙后，这与异常的骨和免疫表型有关。主要目标为 该 K99/R00 提案旨在测试 GAS6 在口腔组织愈合中的关键作用。提出了两个具体目标 根据我们之前的观察。我们假设 GAS6 直接作用于间充质干细胞 使它们向成骨细胞表型做好准备。这个假设将通过愈合测量来检验 在提取缺乏 GAS6 信号传导的小鼠间充质干细胞后，以及相关的 对提取后来自患者的原代细胞进行实验。我们还假设增加 GAS6 缺乏时的中性粒细胞浸润会阻碍软组织愈合。我们将采用条件淘汰赛 中性粒细胞和中性粒细胞功能模型来检验这一假设。 K99部分将致力于 开发用于研究组织和免疫细胞特异性 GAS6 信号传导的新工具，并以我之前的经验为基础 研究成骨细胞生物学，而 R00 部分将部署这些工具来研究炎症并连接 通过 GAS6 信号传导进行肺泡再生。该奖项将为 了解口腔愈合的生理学，同时为候选人提供重要的培训 运用遗传小鼠模型和免疫学，最终成为牙科医师的独立职业 专门治疗全身受损患者的临床医生科学家。