NGF-TrkA Signaling in Dental Implant Osseointegration and Osseoperception

牙种植体骨整合和骨知觉中的 NGF-TrkA 信号传导

• 批准号: 9882982
• 负责人: Ryan Tomlinson
• 金额: $ 15.6万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-02-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9882982
• 关键词: Agonist; Alleles; Antibodies; Area; Axon; Axotomy; Biological Models; Blood Vessels; Cells; Clinical; Data; Dental; Dental Implants; Dental Models; Development; Filament; Food; Fracture; Funding; Future; Goals; Harvest; Histologic; Histology; Immunohistochemistry; Impairment; Implant; Incisor; Knock-in; Knock-out; Knockout Mice; Knowledge; LacZ Genes; Location; Mastication; Maxilla; Measurement; Mechanics; Modeling; Mouse Strains; Mus; Nerve; Nerve Fibers; Nerve Growth Factors; Operative Surgical Procedures; Oral cavity; Orthodontic; Osseointegration; Outcome; Pathway interactions; Patients; Periodontal Ligament; Phosphotransferases; Play; Process; Protocols documentation; Randomized Controlled Clinical Trials; Reporter; Reporting; Research; Role; Signal Transduction; Structure; Techniques; Testing; Therapeutic; TimeLine; Tissues; Tooth Movement; Tooth root structure; Tooth structure; Touch sensation; Transgenes; Trauma; Work; afferent nerve; alveolar bone; base; bone; calcification; chemical genetics; craniofacial; density; follow-up; healing; implantation; improved; in vivo; inferior alveolar nerve; long bone; mechanical load; microCT; mouse model; nerve supply; novel; osteogenic; phase III trial; pre-clinical; primary outcome; response; sensory feedback; small molecule; success; therapeutic target

Project Summary/Abstract The highly innervated periodontal ligament attaches the root of the tooth to alveolar bone and provides tactile sensation to teeth. This sensory feedback, called osseoperception, is critical for controlling tooth contact and manipulating food during mastication. However, the sensory nerves resident in the periodontal ligament are lost when a natural tooth is replaced by a dental implant. As the bone forms a structural and functional connection with the implant, a process known as osseointegration, some sensory nerves have been observed to approach the peri-implant bone. However, it is not known if these sensory nerves contribute to osseointegration or play a role in establishing osseoperception. In this project, our lab will use validated knockout and reporter mice to visualize and disrupt functional signaling of sensory nerves in peri-implant bone in established and novel models of dental implant osseointegration. The long-term goal of our research is to increase the utility and stability of dental implants. In this project, our main objective is to determine the precise timeline and requirement for innervation in peri-implant bone. Our central hypothesis is that sprouting of the craniofacial nerves into the peri- implant bone is critical for the overall stability of the implant and the degree of osseoperception following surgery. We will directly test our hypothesis in two specific aims. In the first aim, we will characterize the expression of NGF as well as TrkA sensory nerve innervation of peri-implant bone during osseointegration of submerged and immediately loaded dental implants using three reporter mouse strains. In the second aim, we will determine the effect of modulating NGF-TrkA signaling on implant osseointegration and osseoperception. NGF-TrkA signaling will be impaired using a chemical-genetic knockout mouse, and stimulated using exogenous NGF. The results of this study will clearly define the requirements of NGF-TrkA signaling for implant osseointegration and provide a pathway for leveraging this signaling axis for improving osseoperception. Importantly, this proposal fits directly into a conceptual framework that will lead to future R01-level funding for this important research area.

项目总结/摘要 高度神经支配的牙周韧带将牙根附着在牙槽骨上， 牙齿的感觉。这种感觉反馈，称为骨感知，对控制牙齿接触至关重要， 在咀嚼过程中操纵食物。然而，牙周膜内的感觉神经却丧失了 当天然牙齿被牙科植入物取代时。当骨头形成结构和功能连接时 通过植入，一个被称为骨整合的过程，已经观察到一些感觉神经接近 种植体周围的骨头然而，尚不清楚这些感觉神经是否有助于骨整合或发挥作用。 在建立骨感知中的作用。在这个项目中，我们的实验室将使用经过验证的敲除和报告小鼠， 在已建立的和新的模型中可视化和破坏种植体周围骨中感觉神经的功能信号传导 牙种植体骨整合的研究。我们研究的长期目标是提高 牙科植入物在这个项目中，我们的主要目标是确定精确的时间轴和要求， 种植体周围骨的神经支配。我们的中心假设是颅面神经的萌芽进入了大脑- 种植体骨对于种植体的整体稳定性和手术后的骨感知程度是至关重要的。 我们将在两个具体目标中直接检验我们的假设。在第一个目标中，我们将描述 种植体周围骨的神经生长因子和TrkA感觉神经支配在种植体骨整合过程中的作用 使用三种报告小鼠品系立即装载牙植入物。在第二个目标中，我们将确定 调节NGF-TrkA信号对种植体骨整合和骨感知的影响。NGF-TrkA信号转导 将使用化学基因敲除小鼠受损，并使用外源性NGF刺激。结果 本研究的结论将清楚地定义NGF-TrkA信号传导对种植体骨整合的要求，并提供 一个利用这个信号轴来改善骨感知的途径。重要的是，这一提议直接适用于 这一概念框架将为这一重要研究领域提供未来R 01级的资金。