DSPP signaling in dentinogenesis

牙本质发生中的 DSPP 信号传导

• 批准号: 10379987
• 负责人: Shuo Chen
• 金额: $ 35.86万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10379987
• 关键词: Affect; Animal Model; Area; Bioinformatics; Biological; Biological Process; Cell Differentiation process; Cell Line; Cell Lineage; Cell Nucleus; Cell Surface Proteins; Cell membrane; Chromatin; Communities; Complex; DNA-Directed RNA Polymerase; DSPP gene; Data; Defect; Dental; Dental Papilla; Dental Pulp; Dental caries; Dentin; Dentin Dysplasia; Dentin Formation; Dentinogenesis; Dentinogenesis Imperfecta; Dentistry; Dentists; Dentition; Development; Disease; Economics; Exhibits; Extracellular Matrix Proteins; Focal Adhesion Kinase 1; Future; Gene Expression; Gene Mutation; Genetic Diseases; Genetic Transcription; Genetically Engineered Mouse; Goals; Health; Hereditary Disease; Histones; Homeostasis; In Vitro; Incidence; Inherited; Integrins; Knock-out; Knockout Mice; Knowledge; Life; Ligand Binding; Ligands; MMP9 gene; Mesenchymal; Molecular; Mutation; National Institute of Dental and Craniofacial Research; Natural regeneration; Nuclear Protein; Nuclear Translocation; Odontoblasts; Outcomes Research; Pathogenesis; Pathway interactions; Peptide Hydrolases; Personal Satisfaction; Persons; Phosphorylation; Play; Population; Process; Protein Kinase; Proteins; Publishing; Pulp Chambers; Quality of life; RGD (sequence); RNA; Reagent; Recording of previous events; Research; Role; Signal Pathway; Signal Transduction; Site; Syndrome; Testing; Thinness; Time; Tooth Attrition; Tooth Components; Tooth Diseases; Tooth structure; United States National Institutes of Health; Up-Regulation; Use of New Techniques; Work; base; conditional knockout; extracellular; in vivo; innovation; integrin beta6; mineralization; mouse model; novel; occludin; overexpression; receptor; recruit; repaired; social; stem cell differentiation; transcription factor

Project summary One of the most important goals of dentistry and the NIDCR/NIH is to generate a whole “Bio- Tooth”. Dentin is a critical structural component of tooth. Although it has made great progress of dentin development benefit for numerous hereditary syndromes and chromosomal anomalies, many gaps have been remained. Understanding signaling pathways of dental mesenchymal lineages and dentin formation would provide an avenue for repair and regeneration of dentin. Dentin sialophosphoprotein (Dspp) is highly expressed in odontoblasts and dentin and processed in to dentin sialoprotein (Dsp) and dentin phosphoprotein (Dpp). Dsp and Dpp mutations are associated with dentinogenesis imperfecta (DGI), which is the most common dentin genetic disorder. Our long-ranged goal is to elucidate the biological mechanisms controlling dentin formation, which will fill a key gap of knowledge leading to dentin regenerating. The objective here is to define the signaling pathways essential for dentinogenesis. Our central hypothesis is that the novel control mechanisms, in which the several signals among Bmp2-pAkt-pErk-Dlx3-Sp7-Gcn5-Dspp as well as Dsp-integrin β6 and Dsp-occludin play synergic roles in controlling dentin formation. The hypothesis is based on our strong preliminary data produced using both global knockout (KO) and conditional KO (cKO) mouse models as well as in vitro cellular and molecule approaches. Three Specific Aims are proposed to test this hypothesis: 1). to determine Bmp2 signaling in Dspp expression and dentin formation. Bmp2 signal plays functional roles: Dspp expression via up- regulation of Bmp2-pAkt-Erk-Dlx3-Sp7-Gcn5G signaling pathways. 2). to rescue dentin formation in Bmp2 KO mice by overexpression of Dspp gene. Due to dramatically decrease of Dspp expression and dentin defect in Bmp2 KO mice, the hypothesis is that Dspp overexpression in Bmp2 KO mice is able to rescue dentin formation. 3). to determine Dsp signaling in dental mesenchymal cell differentiation and dentin formation. Dsp is processed by MMP9 into active fragments, which as ligands bind to cell membrane receptors, integrin β6 and occludin. The Dsp-β6 complex positively stimulates Dspp expression and odontoblast homeostasis through up-regulation of Smad1/5/8 signaling. Dsp-occludin signal enhances phosphorylation of focal adhesion kinase (FAK), promoting dental mesenchymal cell differentiation. The proposed research is innovative because each step of transcription, posttranslational processing and signaling transduction of Dsp/Dspp is necessary for the formation of healthy dentin. Such knowledge will advance our understanding of the pathogenesis of inherited disorders that threaten the structural integrity of dentin and provide a potential clue for treating dental diseases and dentin regeneration.

项目概要 牙科和 NIDCR/NIH 最重要的目标之一是建立一个完整的“生物- 牙”。牙本质是牙齿的重要结构组成部分。虽然在这方面已经取得了长足的进步 牙本质发育有益于多种遗传综合征和染色体异常， 仍然存在许多差距。了解牙齿间充质的信号通路 谱系和牙本质形成将为牙本质的修复和再生提供途径。 牙本质唾液酸磷蛋白 (Dspp) 在成牙本质细胞和牙本质中高表达并加工 形成牙本质唾液蛋白（Dsp）和牙本质磷蛋白（Dpp）。 Dsp 和 Dpp 突变是 与牙本质发育不全（DGI）相关，这是最常见的牙本质遗传病 紊乱。 我们的长期目标是阐明控制牙本质形成的生物学机制，这 将填补导致牙本质再生的关键知识空白。这里的目标是定义 牙本质发生所必需的信号通路。我们的中心假设是新颖的控制 机制，其中 Bmp2-pAkt-pErk-Dlx3-Sp7-Gcn5-Dspp 之间的几个信号以及 Dsp-整合素β6 和Dsp-occludin 在控制牙本质形成中发挥协同作用。这 假设是基于我们使用全局淘汰 (KO) 和 条件 KO (cKO) 小鼠模型以及体外细胞和分子方法。三 提出了具体目标来检验这一假设：1)。确定 Dspp 中的 Bmp2 信号 表达和牙本质形成。 Bmp2 信号发挥功能作用：Dspp 通过上行表达 Bmp2-pAkt-Erk-Dlx3-Sp7-Gcn5G 信号通路的调节。 2）。拯救牙本质形成 通过过度表达 Dspp 基因来敲除 Bmp2 小鼠。由于 Dspp 表达急剧下降 Bmp2 KO 小鼠中存在牙本质缺陷，假设 Bmp2 KO 小鼠中 Dspp 过度表达 能够挽救牙本质的形成。 3）。确定牙科间充质细胞中的 Dsp 信号传导 分化和牙本质形成。 Dsp被MMP9处理成活性片段，如下 配体与细胞膜受体、整合素β6 和occludin 结合。 Dsp-β6 复合物呈阳性 通过上调 Smad1/5/8 刺激 Dspp 表达和成牙本质细胞稳态 发信号。 Dsp-occludin 信号增强粘着斑激酶 (FAK) 的磷酸化， 促进牙齿间充质细胞分化。拟议的研究具有创新性，因为 Dsp/Dspp的转录、翻译后加工和信号转导的每一步都是 形成健康牙本质所必需的。这些知识将增进我们对 遗传性疾病的发病机制威胁牙本质的结构完整性并提供 治疗牙科疾病和牙本质再生的潜在线索。

项目成果

Co-relationships between glandular salivary flow rates and dental caries.

• DOI: 10.1111/ger.12028
• 发表时间: 2014-09
• 期刊: Gerodontology
• 影响因子: 2
• 作者: Diaz de Guillory C;Schoolfield JD;Johnson D;Yeh CK;Chen S;Cappelli DP;Bober-Moken IG;Dang H
• 通讯作者: Dang H

Coordinated expression of p300 and HDAC3 upregulates histone acetylation during dentinogenesis.

p300 和 HDAC3 的协调表达上调牙本质发生过程中的组蛋白乙酰化

• DOI: 10.1002/jcb.29470
• 发表时间: 2020-03
• 期刊: Journal of cellular biochemistry
• 影响因子: 4
• 作者: Tao H;Li Q;Lin Y;Zuo H;Cui Y;Chen S;Chen Z;Liu H
• 通讯作者: Liu H

Differential lncRNA/mRNA Expression Profiling and Functional Network Analyses in Bmp2 Deletion of Mouse Dental Papilla Cells.

• DOI: 10.3389/fgene.2021.702540
• 发表时间: 2021
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Wang F;Tao R;Zhao L;Hao XH;Zou Y;Lin Q;Liu MM;Goldman G;Luo D;Chen S
• 通讯作者: Chen S

In vitro osteogenic differentiation of adipose stem cells after lentiviral transduction with green fluorescent protein.

• DOI: 10.1097/scs.0b013e3181bf04af
• 发表时间: 2009-11
• 期刊: The Journal of craniofacial surgery
• 作者: Wang Q;Steigelman MB;Walker JA;Chen S;Hornsby PJ;Bohnenblust ME;Wang HT
• 通讯作者: Wang HT

Tissue-specific expression of dentin sialophosphoprotein (DSPP) and its polymorphisms in mouse tissues.

• DOI: 10.1016/j.cellbi.2009.05.001
• 发表时间: 2009-08
• 期刊: CELL BIOLOGY INTERNATIONAL
• 影响因子: 3.9
• 作者: Yuan, Guohua;Wang, Yinghua;Gluhak-Heinrich, Jelica;Yang, Guobin;Chen, Lei;Li, Tong;Wu, Li-An;Chen, Zhi;MacDougall, Mary;Chen, Shuo
• 通讯作者: Chen, Shuo