The Role of DPP in Dental Pulp Stem Cells and its Potential in Tissue Regeneration

DPP 在牙髓干细胞中的作用及其在组织再生中的潜力

• 批准号: 10133458
• 负责人: Anne George
• 金额: $ 37.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133458
• 关键词: Actins; Amputation; Biological Assay; Bone Matrix; Calcium; Cell Shape; Cells; Chemicals; Clinical; Complex; Cues; Cytoskeleton; DSPP gene; Data; Dental; Dental Pulp; Dental Pulp Capping; Dental caries; Dentin; Deposition; Disease; Event; Extracellular Matrix; Extracellular Matrix Proteins; F-Actin; Future; Gene Expression; Genetic Transcription; Guanosine Triphosphate Phosphohydrolases; Histology; Immobilization; Immunofluorescence Immunologic; Immunoprecipitation; In Vitro; Injury; Ligands; MAPT gene; Mechanics; Mediating; Methods; Microtubules; Modeling; Molecular; Natural regeneration; Odontoblasts; Phosphoproteins; Property; Proteins; Public Health; Regenerative Medicine; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Signaling Molecule; Site; Small Interfering RNA; Specificity; Stains; Stimulus; Stress Fibers; Structure; Testing; Therapeutic Agents; Time; Tissue Engineering; Tissues; Tooth root structure; Tooth structure; Trauma; Tubular formation; Vascularization; WNT Signaling Pathway; Western Blotting; adult stem cell; base; beta catenin; cell motility; cytokine; cytotoxicity; experimental study; in vivo Model; inhibitor/antagonist; knock-down; migration; mouse model; nerve supply; novel; preservation; programs; receptor; regeneration potential; repaired; response; rho; scaffold; stem cell migration; stem cell population; stem cells; therapy development; tissue regeneration; tissue repair; tissue stem cells; transplant model; wound healing

PROJECT SUMMARY Deep caries and pulp exposures are normally treated by pulp capping or partial pulp amputation to preserve the vitality of the pulp. Control of dental caries is a major public health program. Discovery of the dental pulp stem cells (DPSCs) have opened up new avenues for regeneration or repair of the pulp-dentin complex. The use of adult stem cells for tissue regeneration and repair is important in regenerative medicine. Another important component for tissue engineering is a bioactive signaling molecule. For the last two decades we have been studying the acidic phosphoproteins of the organic matrix of bone and dentin. Besides their function in the extracellular matrix, many of these proteins are now implicated in stimulating signaling events. One such protein identified in the dentin matrix is dentin phosphophoryn (DPP). Until recently, the function of DPP was thought to be structural; however, recent studies have suggested that DPP may have other functions in cell signaling. Our preliminary data indicate that DPP activates the Wnt signaling pathway to promote odontoblast differentiation of the dental pulp stem cells. Wnt5a was the specific Wnt activated by DPP in DPSCs. The downstream effectors of Wnt5a signaling that we propose to investigate are β-catenin, TAZ and RhoC. We hypothesize that these DPP-mediated activation of these effectors are responsible for differentiation of DPSC's and their migratory properties. To test this hypothesis we propose to use molecular approaches : (a) To investigate the molecular mechanisms by which DPP mediates the activation of Wnt signaling to stabilize β-catenin and TAZ resulting in the differentiation of DPSCs into odontoblasts; (b) To examine the influence of DPP stimulation on RhoC GTPase signaling and its effect on the reorganization of the actin cytoskeleton in DPSCs leading to changes in cell shape and migration; (c ) To evaluate DPP as a therapeutic agent in an ectopic model for dentin- pulp regeneration. Overall, results from these studies would reveal an unprecedented signaling framework modulated by DPP that could be utilized in the future to develop therapies to restore lost damaged or diseased dentin-pulp complex with a vital pulp leading to tooth survival.

项目总结 深龋和牙髓外露通常采用盖髓或部分髓治疗。 截肢以保持牙髓的活力。控制龋齿是一项主要的公共事业 健康计划。牙髓干细胞(DPSCs)的发现开辟了新的 再生或修复牙髓-牙本质复合体的途径。成体茎的利用 用于组织再生和修复的细胞在再生医学中非常重要。另一个 组织工程的重要组成部分是生物活性信号分子。对于 在过去的二十年里，我们一直在研究有机物中的酸性磷酸蛋白 骨和牙本质的基质。除了它们在细胞外基质中的功能外，许多 这些蛋白质现在被认为与刺激信号事件有关。一种这样的蛋白质 牙本质基质中鉴定的是牙本质磷蛋白(DPP)。直到最近，该函数 民进党被认为是结构性的；然而，最近的研究表明，民进党 可能在细胞信号传递中具有其他功能。我们的初步数据显示，民进党 激活Wnt信号通路促进成牙本质细胞分化 牙髓干细胞。Wnt5A是DPP在DPSCS中激活的特异性Wnt。这个 我们建议研究的WNT5a信号的下游效应是β-连环蛋白， 塔兹和RHOC。我们假设这些DPP介导的这些效应器的激活 负责区分DPSC及其迁移特性。为了测试这一点 假设我们建议使用分子方法：(A)研究分子 DPP介导Wnt信号激活稳定β-连锁素的机制 和TAZ诱导DPSCs分化为成牙本质细胞； DPP刺激对RhoC GTP酶信号转导的影响及其在细胞内的作用 DPSCs中肌动蛋白细胞骨架的重组导致细胞形状和 迁移；(C)在牙本质异位模型中评价DPP作为治疗剂- 牙髓再生。总体而言，这些研究的结果将揭示出前所未有的 受DPP调控的信号框架，可用于未来的治疗 用有活力的牙髓修复丢失的受损或患病的牙本质-牙髓复合体 生死存亡。