GAS6-mediated alveolar bone regeneration

GAS6介导的牙槽骨再生

• 批准号: 10607169
• 负责人: Ann Marie Decker
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607169
• 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; 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; Testing; Therapeutic; Tissues; Tooth Loss; Training; Trauma; Traumatic injury; Work; alveolar bone; base; bone; bone repair; 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; regenerative approach; regenerative repair; 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.

项目摘要 由创伤或疾病引起的牙齿缺失仍然是一个重要的世界性问题，这是由于美学差和牙齿缺失。 功能解决这个问题并不简单，因为牙槽骨和口腔组织的再生并不容易。 这是可以预测的，部分原因是过程的复杂性。这些缺损的骨再生仍然存在 不可预测的和理解的生理机制，指导骨髓生物学， 炎症消退将在未来增加这些再生技术的治疗可靠性。 我们已经观察到生长抑制特异性6（GAS 6）在控制牙槽骨中的一个先前未知的作用 和软组织再生。GAS 6缺陷小鼠的愈合情况明显较差 提取后，这与异常的骨和免疫表型有关。的首要目标 这个K99/R 00提案是为了测试GAS 6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GAS 6直接作用于间充质干细胞， 使它们向成骨细胞表型转化。这一假设将通过测量愈合进行检验 在用GAS 6信号传导缺陷的间充质干细胞提取小鼠后，沿着相关的 对提取后来源于患者的原代细胞进行的实验。我们还假设， GAS 6缺乏中中性粒细胞浸润阻碍软组织愈合。我们将采用条件性击倒 中性粒细胞和中性粒细胞功能的模型来检验这一假设。K99部分将致力于 开发新的工具来研究组织和免疫细胞特异性GAS 6信号传导，并建立在我以前的基础上， 在成骨细胞生物学工作，而R 00部分将部署这些工具来研究炎症和连接 肺泡再生与GAS 6信号。这一奖项将为我们提供一个重要的贡献。 了解口腔愈合的生理学，同时为候选人提供重要的培训 在使用遗传小鼠模型和免疫学，最终导致一个独立的职业生涯作为一个牙科医生， 专门治疗全身性损害患者的临床医生-科学家。