Individual Predoctoral Dental Scientist Fellowship

个人博士前牙科科学家奖学金

基本信息

批准号：
8511363
负责人：
Angela Gullard
金额：
$ 4.8万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8511363
关键词：
Address Age Binding Sites Biochemical Biological Assay Biological Process Bone Marrow Bone Matrix C-terminal Cell Proliferation Cells Collagen Collagen Type I DSPP gene Dental Dental Papilla Dental Pulp Dental Pulp Calcification Dental caries Dentin Dentin Formation Dentinogenesis Dentition Development Disease Doctor of Philosophy Elements Enamel Organ Epithelium Event Extracellular Matrix Extracellular Matrix Proteins Family Family member Fellowship Fibrosis Foundations Functional disorder Gene Expression Gene Expression Regulation Genetic Glycoproteins Growth Factor Health Hormones Human In Vitro Individual Inherited Integrin Binding Laboratories Lead Ligands Limb structure Link Literature Mammals Mediating Mesenchymal Minerals Modeling Molecular Morphology Mus Muscle Weakness Mutation Odontoblasts Online Mendelian Inheritance In Man Oral Osteoblasts Pain Patients Pattern Peptides Phenotype Physiologic calcification Play Point Mutation Process Progressive Diaphyseal Dysplasia Property Proteins Regulation Reporting Research Research Training Role School Dentistry Scientist Sexual Development Signal Transduction Skeleton Specimen Staging Stem cells Syndrome System TGFB1 gene Tertiary Protein Structure Testing Therapeutic Tissues Tooth structure Transforming Growth Factors Transgenic Mice Transgenic Model Transgenic Organisms Up-Regulation Work bone bone morphogenetic protein 2 bone sialoprotein cellular pathology cranium cytokine density dentin matrix protein 1 dentinal phosphophoryn enhancing factor human TGFB1 protein inorganic phosphate kidney vascular structure long bone member mineralization molecular pathology mouse model novel novel diagnostics novel therapeutics osteopontin overexpression pre-doctoral programs promoter protein expression skeletal skeletal disorder skeletogenesis soft tissue tomography tool

项目摘要

DESCRIPTION (provided by applicant): Currently, very little is known regarding tissue-specific gene regulation during the later stages of tooth development, especially those associated with dentin mineralization. Recent studies have identified transforming growth factor-beta 1 (TGF21) as a potential modulator of primary dentin extracellular matrix (DECM) formation. TGF21 has been shown to initiate odontoblast cytodifferentiation from immature dental papilla mesenchymal cells. Initially secreted by enamel organ epithelium, TGF21 has been shown to be upregulated in dentin-producing odontoblasts during primary dentinogenesis and become incorporated into the DECM. In mature odontoblasts, however, TGF21 has been shown to downregulate DECM proteins such as dentin matrix protein-1 (DMP-1) and dentin sialophosphoprotein (DSPP), two of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family of bone/dentin matrix proteins. Matrix extracellular phosphoglycoprotein (MEPE), the least characterized SIBLING member in teeth, seems to have controversial roles in mineralization. Preliminary studies demonstrate that TGF21 dysregulates SIBLING protein and gene expression in the dentin layer and in pulp cells of a novel transgenic mouse model for Camurati-Engelmann disease (CED). CED, though rare, is most often due to a point mutation in the TGFB1 gene leading to overexpression of the mature, active TGF21 molecule. Patients with CED present with severe bone thickening and subsequent soft tissue compression. Transmitted through autosomal dominant inheritance, CED in humans has not been previously reported to be associated with dental abnormalities. Our hypothesis is that the transgenic CED mouse model displays abnormal dentin formation as mediated by altered expression of the SIBLINGs, in particular MEPE, caused by the overexpression of mature TGF21. The specific aims seek to identify the signaling effects that overexpression of TGF21 has on dentin matrix formation and maturation, to clarify the function of MEPE in dentin mineralization, and to determine the way in which TGF21 regulates Mepe expression. Novel mouse models and in vitro systems will be used and characterized by way of radiographic and mineral density microcomputed tomography examinations, along with biochemical and functional assays. The information obtained from these studies will provide a foundation for understanding the molecular mechanisms involved in both normal and pathological dentin development. Eventually the proposed studies will facilitate the development of novel diagnostic tools and therapeutic treatments for patients with dental caries, various tooth/bone mineralization disorders, or syndromes with altered dentin formation. This research will elucidate the role of tooth/bone matrix material properties in oral and skeletal health and disease.

描述（由申请人提供）：目前，关于牙齿发育后期的组织特异性基因调节，尤其是与牙本质矿化相关的基因的调节知之甚少。最近的研究已经确定了转化生长因子-beta 1（TGF21）是原发性牙本质外基质（DECM）形成的潜在调节剂。 TGF21已显示可引发未成熟牙皮乳头间充质细胞的胞素细胞细胞分化。 TGF21最初由搪瓷器官上皮分泌，在原发性牙本质发生过程中已显示在产生牙本质的牙糖细胞中上调，并掺入DECM中。然而，在成熟的odontoblasts中，TGF21已被证明可以下调DECM蛋白，例如牙本质基质蛋白-1（DMP-1）和Dentin sialophophoplotein（DSPP），这是两个小的整联蛋白结合的小体和N-CRINGING N-COND N-COND N-CRINGed N-CRINGed GYCOPROTOTION（SIBLING）骨/dentent蛋白蛋白质蛋白质蛋白质蛋白。基质外磷脂蛋白（MEPE）是牙齿中特征最少的同级成员，似乎在矿化中具有有争议的作用。初步研究表明，TGF21在牙本质层中的兄弟姐妹蛋白和基因表达失调，在新型的转基因小鼠模型的牙本质细胞中，用于Camurati-Engelmann疾病（CED）。 CED虽然很少见，但通常是由于TGFB1基因中的一个点突变导致成熟的活性TGF21分子过表达。 CED患者的骨增厚和随后的软组织压缩。通过常染色体显性遗传传播，以前尚未据报道与牙齿异常有关。我们的假设是，转基因CED小鼠模型显示出异常的牙本质形成，是由于兄弟姐妹的表达改变，特别是由成熟TGF21的过表达引起的介导的。具体目的旨在确定TGF21过表达对牙本质基质形成和成熟的信号传导效应，以阐明MEPE在牙本质矿化中的功能，并确定TGF21调节MEPE表达的方式。新型小鼠模型和体外系统将通过放射线和矿物质密度微型层析成像检查以及生化和功能测定法使用和表征。从这些研究中获得的信息将为理解正常和病理牙本质发育涉及的分子机制提供基础。最终，拟议的研究将促进针对龋齿，各种牙齿/骨矿化疾病或牙本质形成改变的综合征的新型诊断工具和治疗性治疗的开发。这项研究将阐明牙齿/骨基质材料在口腔和骨骼健康和疾病中的作用。