Neurobiological control of periodontal homeostasis through microRNA, TGF-beta, and Wnt signaling

通过 microRNA、TGF-β 和 Wnt 信号传导对牙周稳态的神经生物学控制

• 批准号: 9756189
• 负责人: Tom Diekwisch
• 金额: $ 15.39万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-04 至 2020-02-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756189
• 关键词: Affect; Animal Model; Animals; Ankylosis; Bioinformatics; Biological Assay; Bone Regeneration; Bone remodeling; Cicatrix; Collagen; Cytoskeletal Modeling; Cytoskeletal Proteins; Data; Data Set; Defect; Dentition; Diagnostic radiologic examination; Down-Regulation; Emotional; Engineering; Epithelial; Epithelial Cells; G-Protein-Coupled Receptors; Galanin; Ganglia; Gene Expression; Gene Expression Profiling; Goals; Health; Height; Homeostasis; Hybrids; In Vitro; Interruption; Jaw; Laboratories; Messenger RNA; MicroRNAs; Modeling; Nanosphere; Nerve; Nerve Fibers; Neurobiology; Neuropeptides; Operative Surgical Procedures; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Outcome; Pathway interactions; Patients; Peptides; Periodontal Diseases; Periodontal Ligament; Periodontal Pocket; Periodontitis; Periodontium; Phenotype; Prevention; Proteins; Rattus; Research; Rest; Reverse Transcriptase Polymerase Chain Reaction; Roentgen Rays; Role; Sensory; Signal Transduction; Signaling Molecule; Testing; Tissue Engineering; Tissues; Tooth Ankylosis; Tooth structure; Transforming Growth Factor beta; Trigeminal nerve structure; Up-Regulation; WNT Signaling Pathway; Walkers; alveolar bone; base; bone; clinically significant; craniofacial bone; design; glycogen synthase kinase 3 beta; inferior alveolar nerve; inhibitor/antagonist; innovation; mandibular nerve; mineralization; nerve supply; nerve transection; osteoclastogenesis; osteogenic; prevent; progenitor; response; sample fixation; skeletogenesis; soft tissue; spatial relationship; trend

The periodontium is a richly innervated tissue that undergoes continuous modelling and remodeling by alveolar bone osteoblasts, osteocytes, and osteoclasts. Studies from our laboratory have demonstrated a close spatial relationship between trigeminal nerve ganglia and the Epithelial Rests of Malassez (ERM), an epithelial cell network residing within the non-mineralized periodontal ligament. Inferior alveolar nerve (IAN) transection studies resulting in dento-alveolar ankylosis and a reduction in ERM have confirmed the essential role of sensory innervation for periodontal homeostasis. For the present application, we have established the IAN transection model in our laboratory and provided radiographic evidence for enhanced mineralization and ankylosis in the periodontal region of rat molars. Gene expression profiling comparing IAN transected and control tissues demonstrated an unexpected 28-fold significant increase in galanin (GAL) and a more than two-fold decrease in the TGF-β signaling molecules Smad2, Smad3 and Tgf-β1, and the Wnt inhibitors Dkk1, Dkk2 and Gsk-3β. In the same IAN transection group, microRNA miR-92b expression was more than two-fold upregulated, as verified via miRNA profiling and RT-PCR. MiR-92b upregulation after IAN transection in conjunction with bioinformatics data implicating Wnt and Tgf-β as possible miR-92b targets prompted us to speculate that GAL affects its skeletogenic downstream effects through miR-92b. In vitro studies revealed that GAL treatment promoted osteogenic differentiation of PDL progenitors and increased mineralization, while reducing osteoclastogenesis of BMMCs. Block of RhoA or application of GAL antagonist affected PDL cytoskeletal organization and gene expression, indicating that GAL functions through G protein coupled receptors. IWhen applied to periodontal pockets of animals suffering from periodontitis, GAL tissue engineering constructs accomplished a 20% increase in alveolar bone levels compared to controls, resulting in a clinically significant increase in alveolar bone height. Based on this promising new set of data we have designed a research plan to define the role of GAL in response to IAN transection, determine the mechanism underlying its effect on skeletogenesis, and exploit its applicability for bone regeneration and the prevention of periodontal ankylosis. The overall goal of our research plan is to test the hypothesis that periodontal nerves affect alveolar bone homeostasis through a GAL–GPCR–miR-92b–TGF-β/Wnt regulatory loop and that application of GAL neurosecretory peptides will stimulate Wnt signaling and new bone formation. We anticipate that the outcomes of our study will lead to innovative neuropeptide based/engineering hybrid approaches that will restore periodontal health in millions of patients and prevent the emotional and functional scars associated with lost teeth and incomplete dentitions.

牙周组织是一个神经支配丰富的组织，它经历了持续的塑造和重塑