Intracellular and Extracellular function of dentin phosphophoryn

牙本质磷酸蛋白的细胞内和细胞外功能

• 批准号: 8269568
• 负责人: Anne George
• 金额: $ 38.86万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269568
• 关键词: Actins; Adhesions; Adhesives; Affinity; Alveolar; Amino Acids; Aspartic Acid; Binding; Biological Process; Bone Matrix; Calcium; Calmodulin; Cell Proliferation; Cell Survival; Cell membrane; Cell physiology; Cells; Charge; Collagen; Collagen Fiber; Collagen Fibril; Complex; Crystal Formation; Cytoskeleton; Dentin; Dentin Formation; Dentinogenesis; Deposition; Development; Embryo; Event; Exhibits; Extracellular Matrix; Gel; Gene Expression; Gene Proteins; Gene Targeting; Genes; Genetic Transcription; Goals; Growth; Growth and Development function; Human; Hydroxyapatites; In Vitro; Inorganic Chemicals; Integrin Binding; Integrins; Ions; Kidney; Knowledge; Lead; Life; Ligation; Location; Lung; Mechanics; Mediating; Mesenchymal; Minerals; Mitogen-Activated Protein Kinases; Molecular; Morphology; Mus; Musculoskeletal; Natural regeneration; Neural Crest; Neural Crest Cell; Nuclear Translocation; Odontoblasts; Organism; Phase; Phosphoproteins; Phosphorylation; Phosphotransferases; Physiologic calcification; Play; Precipitation; Process; Production; Property; Protein Biosynthesis; Proteins; RGD (sequence); Reporting; Role; Second Messenger Systems; Serine; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Staging; Stem cells; Structure; Temperature; Testing; Time; Tissues; Tooth structure; Vertebrates; biomineralization; bone; calcium phosphate; calmodulin-dependent protein kinase II; cell type; demineralization; extracellular; in vivo; insight; interest; macromolecule; mineralization; phosphophoryn; pressure; public health relevance; receptor; response; scaffold; second messenger

DESCRIPTION (provided by applicant): The proper mineralization of bones and teeth has great importance in normal human growth and development and musculoskeletal function. Disruption of normal biomineralization can lead to pathological mineralization or demineralization process. Understanding the complex process of biomineralization relies on knowledge of the structure and function of the organic matrix of mineralized tissues. Acidic phosphoproteins of the organic matrix of bone and dentin have been implicated as regulators of the nucleation process and growth of the inorganic calcium phosphate crystals of bone and teeth in vertebrates. The odontoblasts, which are dentin forming cells are neural crest derived and produce a unique set of phenotypic products. One such protein identified in the dentin matrix is dentin phosphophoryn (DPP). DPP isolated from dentin, has a unique composition with aspartyl and seryl residues comprising at least 75% of the amino acids with 85-90% of the serines being phosphorylated. 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. Therefore, the proposed studies are highly significant as it will provide important mechanistic insights into the function of DPP and its effects on cellular functions and in biological processes such as dentin biomineralization. We hypothesize that DPP is essential for the survival, terminal differentiation of the odontoblasts and in the mineralization of the organic matrix. To test this hypothesis we propose to use molecular approaches to: (a) investigate DPP-mediated adhesive signaling events leading to activation of cell proliferation and survival; (b) identify the mechanism by which DPP activates Smad1 and the downstream transcriptional responses leading to odontoblast terminal differentiation; (c) elucidate the role of DPP in mediating nucleation and growth of hydroxyapatite. Progress in understanding the function of DPP from the perspective of matrix mineralization and signaling has broad ramifications in the field of biomineralization. PUBLIC HEALTH RELEVANCE: During tooth development, the preodontoblasts polarize and elongate as they mature to the secretory form and secrete collagen and a variety of noncollagenous proteins. The major acidic phosphoprotein synthesized by the odontoblasts is "dentin phosphophoryn" DPP. DPP is a highly acidic protein and has been implicated to function as a regulator of mineral deposition during dentin formation. In this proposal we intend to identify the mechanism by which DPP functions in the extracellular matrix as a regulator of mineralization and intracellularly as a cell signaling molecule. DPP mediated signaling can regulate odontoblast proliferation and differentiation. Results from this study should help us define the various functions of DPP, and its potential use in dentin regeneration.

描述（由申请人提供）：骨骼和牙齿的适当矿化在正常的人类生长和发育以及肌肉骨骼功能方面非常重要。正常生物矿化的破坏会导致病理矿化或去矿化过程。了解生物矿化的复杂过程取决于对矿化组织有机基质的结构和功能的了解。骨和牙本质的有机基质的酸性磷蛋白已被认为是脊椎动物中骨和牙齿的无机磷酸钙晶体的成核过程的调节剂和生长。牙本质形成细胞的牙糖细胞是神经rest衍生的，并产生了一组独特的表型产物。在牙本质基质中鉴定出的一种蛋白质是牙本质磷酸化（DPP）。从牙本质中分离出的DPP具有独特的组成，其伴有天冬氨酸和塞里亚残基，其中含有至少75％的氨基酸，其中85-90％的丝氨酸被磷酸化。直到最近，DPP的功能被认为是结构性的。但是，最近的研究表明，DPP在细胞信号传导中可能具有其他功能。因此，拟议的研究非常重要，因为它将为DPP的功能及其对细胞功能的作用以及在诸如牙本质生物矿化等生物学过程中的作用提供重要的机械见解。我们假设DPP对于Odontoblasts的存活，末端分化以及有机基质的矿化至关重要。为了检验该假设，我们建议使用分子方法：（a）研究DPP介导的粘合信号传导事件，导致细胞增殖和生存激活； （b）确定DPP激活SMAD1的机制和导致Odontoblast末端分化的下游转录响应； （c）阐明了DPP在介导成核和羟基磷灰石生长中的作用。从基质矿化和信号传导的角度理解DPP功能的进展在生物矿化领域具有广泛的分析。 公共卫生相关性：在牙齿发育过程中，prodontoblasts在成熟到分泌形式并分泌胶原蛋白和各种非胶原蛋白时会极化和细长。由Odontoblasts合成的主要酸性磷蛋白是“ Dentin Phophophoryn” DPP。 DPP是一种高度酸性的蛋白质，已与牙本质形成过程中的矿物沉积调节剂有关。在此提案中，我们打算确定DPP在细胞外基质中起作用的机制，作为矿化的调节剂，并将细胞内作为细胞信号分子。 DPP介导的信号传导可以调节Odontoblast的增殖和分化。这项研究的结果应有助于我们定义DPP的各种功能及其在牙本质再生中的潜在用途。