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Mechanisms regulating afferent innervation in the dental pulp

调节牙髓传入神经支配的机制

基本信息

批准号：
10214592
负责人：
Sarah Peters
金额：
$ 24.63万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214592
关键词：
Adult Automobile Driving Axon Biological Assay Cells Cementoclast Chronic Disease Coculture Techniques Complex Data Defect Dental Dental Pulp Dental caries Dental crowns Dentin Deposition Development Developmental Gene Embryo Endodontics Enterobacteria phage P1 Cre recombinase Eph Family Receptors Epithelial Exposure to Extracellular Matrix Proteins Future Ganglia Generations Genetic Transcription Goals Image In Vitro Injury Investigation Knockout Mice Laboratories Life Maintenance Mediating Mesenchymal Mesenchyme Modeling Mus Mutant Strains Mice NTN1 gene Natural regeneration Nerve Nerve Fibers Nerve Regeneration Nervous system structure Neurites Neurons Odontoblasts Organ Organism Pain Pain management Paracrine Communication Pathway interactions Pattern Penetration Perinatal mortality demographics Phosphoproteins Plant Roots RNA Reader Recombinants Regulation Reporting Research Role Sensory Signal Transduction Stimulus Structure Structure of trigeminal ganglion Temperature Testing Therapeutic Tissues Tooth Germ Tooth structure Trigeminal nerve structure Viral Visualization afferent nerve axon guidance axonal sprouting base bone experimental study ganglion cell improved in vivo knock-down mRNA sequencing migration mouse model mutant nerve stem cell nerve supply neuroblast neurogenesis neuron development neurotransmission neurotrophic factor new therapeutic target osteopontin overexpression postnatal postnatal development preservation pressure promoter regenerative approach response skeletal

项目摘要

Project Summary/Abstract Since teeth are exposed to environmental stimuli, tooth innervation is crucial to their protection and usage throughout the life of an organism. The tooth is primarily innervated with sensory nerve fibers from the trigeminal ganglion (TG) that protect the tooth organ by relaying noxious stimuli. The dental pulp (DP) secretes neurotrophic factors to guide axonal penetration and sprouting within the tooth during postnatal development in a highly regulated manner. Research has shown that secreted phosphoprotein, osteopontin (OPN), promotes neuronal migration, proliferation, and survival [2–6]. The long-term goal of this project is to understand the mesenchymal-neuronal signals that promote and maintain sensory innervation of the teeth. The overall objective is to determine the role of DP in regulating tooth innervation during development and regeneration. Our central hypothesis is that Tgfbr2 in the dental mesenchyme governs paracrine signaling via OPN to guide tooth sensory innervation. Our laboratory has established a mouse model in which Tgfbr2 is conditionally deleted in odontoblast-producing mesenchyme using an osterix promoter driven Cre recombinase (Tgfbr2cko). These mice survive postnatally but with significant defects in bones and teeth [7,8]. We performed an mRNA- Seq analysis using control and mutant postnatal day 7 DP and found that neuronal maintenance and developmental genes were most highly regulated, including OPN. Immunofluorescent images indicated reduced innervation throughout the DP in Tgfbr2cko mice. Preliminary experiments with DP and primary TG nerves demonstrated increased axonal sprouting when TG cells were cultured with DP. Guided by these data, we will test our hypothesis with the following two specific aims: 1) test the hypothesis that Tgfbr2 is necessary to promote sensory innervation; 2) test the hypothesis that OPN signaling from the DP guides sensory innervation. In both aims, we propose to cross Tg(Thy1-YFP)16Jrs mice, which express a high level of YFP throughout the nervous system [9] to optimize visualization of the neurons. Under the first aim, a well- characterized neurite outgrowth assay will first be used to co-culture TG neurons with DP where Tgf signals are manipulated in the DP. In the second part of the first aim, we will use an in vivo dental injury model and investigate neuronal regeneration in Tgfbr2cko and WT mice. Under the second aim, we will similarly co-culture TG neurons with OPN-deleted DP cells +/- TGF1 and Tgfbr2-deleted cells supplemented with recombinant OPN to investigate developmental neurogenesis in the DP. We will perform the dental injury assay on OPN-/- mice to examine the mechanisms driving neuronal regeneration. The proposed research is significant because it is expected to advance and expand understanding of how DP cells protect the tooth organ via axonal guidance mechanisms. Such information will enhance our understanding of the complex interplay of mesenchymal-neuronal interactions in the tooth that could serve as a basis for future preventative, therapeutic, and regenerative strategies in endodontics and improve the preservation of teeth.

项目总结/文摘