Dental Follicle: A Central Regulator of Tooth Root Formation and Regeneration

牙囊：牙根形成和再生的中央调节器

基本信息

批准号：
10490624
负责人：
Wanida Ono
金额：
$ 37.49万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10490624
关键词：
Ablation Alleles Alveolar Apical Area Biology CXC Chemokines CXCL12 gene Cell Therapy Cells Cementoblast Characteristics Defect Dental Dental Cementum Dental Pulp Dental Sac Dental caries Dentin Epithelial Epithelial Cells Erinaceidae Etiology FOXF1 gene Face Foxes Future Gene Expression Profiling Generations Genes Goals Growth and Development function In Situ In Vitro Intake Knowledge Ligands Ligature LoxP-flanked allele Mastication Mediating Mesenchymal Mesenchymal Stem Cells Modeling Molecular Natural regeneration Odontoblasts Operative Surgical Procedures Osteoblasts Pathway interactions Periodontal Diseases Periodontal Ligament Periodontitis Periodontium Physiological Plant Roots Play Population Population Heterogeneity Prognosis Prosthesis Role SHH gene Signal Transduction Stromal Cell-Derived Factor 1 Structure Structure of periapical tissue System Testing Tissues Tooth Components Tooth Diseases Tooth Loss Tooth regeneration Tooth root structure Tooth structure Toxin Transplantation Validation WNT Signaling Pathway Work alveolar bone base beta catenin bone cell type comparative experimental study in vivo insight nutrition parathyroid hormone-related protein precursor cell regenerative therapy single-cell RNA sequencing stem cells tongue papilla transcription factor transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT The tooth root is a critical component of the tooth, anchored to surrounding alveolar bones through the periodontal ligament (PDL). Appropriate formation of the root and its surrounding structure is essential not only for fundamental functions of the tooth in mastication for nutrition intake, but also for growth and development of the lower face. Prevalent dental diseases such as caries and periodontal diseases are the etiology for tooth loss, which can be treated only by prostheses lacking functional structures, leading to compromised long-term prognosis. An effective approach to regenerate a functional periodontal attachment apparatus is needed to achieve a breakthrough in dental regenerative therapies. During tooth root formation, the dental follicle (DF) provides precursor cells for cementoblasts, periodontal ligament (PDL) cells and alveolar cryptal bone osteoblasts to establish the functional periodontal attachment apparatus, the periodontium. Currently, how diverse populations of dental root mesenchymal progenitor cells work together and generate highly functional tooth roots remains unknown. In this proposal, we will define how concerted actions of distinct classes of dental root mesenchymal progenitor cells are essential for proper formation and regeneration of the tooth root accompanied by a functional periodontal attachment apparatus. In Aim 1, we will define how Hedgehog-Fox pathway regulates DF mesenchymal progenitor cells. We hypothesize that the Forkhead (Fox) transcription factors play a key role in regulating physiological functions of Hedgehog-responsive DF mesenchymal progenitor cells. We will first reveal the diversity of Hedgehog-responsive Gli1+ DF cells using single cell RNA- seq analyses, and determine their relationships with PTHrP+ DF cells and other precursor cell populations. Second, we will determine the function of Gli1+, PTHrP+ and Runx2+ cells in periodontium formation using inducible cell ablation experiments, and further test the function of Foxf1 and Foxf2 in periodontium formation using their floxed alleles. In Aim 2, we will identify Wnt-mediated roles of apical root mesenchymal progenitor cells in tooth root formation. We hypothesize that chemokine (C-X-C motif) ligand 12 (CXCL12)+ mesenchymal progenitor cells in the apical root area orchestrate formation of the tooth root and the apical periodontium in a canonical Wnt signaling-mediated manner. We will determine the relationship between CXCL12+ cells and stem cells for apical papilla (SCAP) using ex vivo culture system, and define molecular mechanisms underlying a Wnt-mediated cell fate choice of mesenchymal progenitor cells by a comparative RNA-seq analysis followed by in situ validation. In Aim 3, we will determine actions of dental root mesenchymal progenitor cells in periodontal regeneration. We hypothesize that distinct classes of dental root mesenchymal progenitor cells contribute to regeneration in a concerted manner. We will define how descendants of Gli1+, PTHrP+, Runx2+ and CXCL12+ progenitor cells contribute to periodontal regeneration after bone destruction, by utilizing a ligature-induced periodontitis model mimicking periodontal diseases, and a surgical periodontal defect model.

项目概要/摘要牙根是牙齿的重要组成部分，通过牙槽骨固定在周围的牙槽骨上。牙周膜（PDL）。根及其周围结构的适当形成不仅至关重要用于牙齿咀嚼、营养摄入的基本功能，还用于牙齿的生长和发育下脸。龋齿、牙周病等常见牙科疾病是牙齿健康的病因。损失，只能通过缺乏功能结构的假肢来治疗，从而导致长期受损预后。需要一种有效的方法来再生功能性牙周附着装置在牙齿再生治疗方面取得突破。在牙根形成过程中，牙囊（DF）提供成牙骨质细胞、牙周膜 (PDL) 细胞和牙槽隐骨的前体细胞成骨细胞建立功能性牙周附着装置，即牙周膜。目前，如何不同群体的牙根间充质祖细胞协同工作并产生高功能牙根仍然未知。在本提案中，我们将定义不同类别的协调行动如何牙根间充质祖细胞对于牙根的正常形成和再生至关重要附有功能性牙周附着装置。在目标 1 中，我们将定义 Hedgehog-Fox 如何通路调节 DF 间充质祖细胞。我们假设 Forkhead (Fox) 转录因素在调节Hedgehog反应性DF间充质细胞的生理功能中起关键作用祖细胞。我们将首先使用单细胞 RNA- 揭示 Hedgehog 响应 Gli1+ DF 细胞的多样性 seq 分析，并确定它们与 PTHrP+ DF 细胞和其他前体细胞群的关系。其次，我们将使用以下方法确定 Gli1+、PTHrP+ 和 Runx2+ 细胞在牙周形成中的功能：诱导细胞消融实验，进一步检测Foxf1和Foxf2在牙周形成中的功能使用他们的 floxed 等位基因。在目标 2 中，我们将确定根尖根间充质祖细胞的 Wnt 介导作用牙根形成过程中的细胞。我们假设趋化因子（C-X-C 基序）配体 12 (CXCL12)+ 间充质根尖区的祖细胞协调牙根和根尖牙周组织的形成典型的 Wnt 信号介导方式。我们将确定 CXCL12+ 细胞与使用离体培养系统进行心尖乳头干细胞（SCAP），并定义其潜在的分子机制通过比较 RNA-seq 分析对间充质祖细胞进行 Wnt 介导的细胞命运选择通过现场验证。在目标 3 中，我们将确定牙根间充质祖细胞在牙周再生。我们假设不同类别的牙根间充质祖细胞以协调一致的方式促进再生。我们将定义 Gli1+、PTHrP+、Runx2+ 的后代如何 CXCL12+ 祖细胞通过利用模拟牙周疾病的结扎诱导牙周炎模型和手术牙周缺损模型。