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: 8089541
• 负责人: Anne George
• 金额: $ 38.07万
• 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/8089541
• 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对于人类正常生长发育以及肌肉骨骼功能非常重要。正常生物矿化的破坏可能导致病理性矿化或脱矿过程。了解生物矿化的复杂过程依赖于对矿化组织有机基质的结构和功能的了解。骨骼和牙本质有机基质的酸性磷蛋白被认为是脊椎动物骨骼和牙齿的无机磷酸钙晶体的成核过程和生长的调节剂。成牙本质细胞是牙本质形成细胞，源自神经嵴，并产生一组独特的表型产物。在牙本质基质中鉴定出的一种这样的蛋白质是牙本质磷酸蛋白（DPP）。从牙本质中分离出来的 DPP 具有独特的组成，其中含有至少 75% 的氨基酸和 85-90% 的丝氨酸被磷酸化的天冬氨酰和丝氨酰残基。直到最近，民进党的职能还被认为是结构性的。然而，最近的研究表明，DPP 可能在细胞信号传导中具有其他功能。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和牙本质生物矿化等生物过程的影响提供重要的机制见解。我们假设 DPP 对于成牙本质细胞的存活、终末分化以及有机基质的矿化至关重要。为了检验这一假设，我们建议使用分子方法来：（a）研究 DPP 介导的粘附信号传导事件，从而导致细胞增殖和存活的激活； (b) 确定 DPP 激活 Smad1 的机制以及导致成牙本质细胞终末分化的下游转录反应； (c) 阐明 DPP 在介导羟基磷灰石成核和生长中的作用。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影响。 公共健康相关性：在牙齿发育过程中，前成牙本质细胞在成熟为分泌形式时极化和伸长，并分泌胶原蛋白和各种非胶原蛋白。成牙本质细胞合成的主要酸性磷蛋白是“牙本质磷酸蛋白”DPP。 DPP 是一种高酸性蛋白质，在牙本质形成过程中起着矿物质沉积调节剂的作用。在本提案中，我们打算确定 DPP 在细胞外基质中作为矿化调节剂以及在细胞内作为细胞信号分子发挥作用的机制。 DPP 介导的信号传导可以调节成牙本质细胞的增殖和分化。这项研究的结果应该有助于我们定义 DPP 的各种功能及其在牙本质再生中的潜在用途。