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Intracellular and Extracellular function of dentin phosphophoryn

牙本质磷酸蛋白的细胞内和细胞外功能

基本信息

批准号：
8465207
负责人：
Anne George
金额：
$ 37.3万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8465207
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

项目摘要

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.

描述(申请人提供)：骨骼和牙齿的适当矿化对人类的正常生长发育和肌肉骨骼功能非常重要。破坏正常的生物矿化可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。骨和牙本质有机基质中的酸性磷蛋白被认为是脊椎动物骨和牙齿中无机钙磷酸盐晶体成核过程和生长的调节因子。成牙本质细胞是牙本质形成细胞，是神经脊来源的，能产生一套独特的表型产物。牙本质基质中发现的一种这样的蛋白质是牙本质磷蛋白(DPP)。DPP从牙本质中分离出来，具有独特的组成，天冬氨酸基和丝氨基残基至少占氨基酸的75%，85%-90%的丝氨酸被磷酸化。直到最近，DPP的功能还被认为是结构性的；然而，最近的研究表明，DPP可能在细胞信号转导中具有其他功能。因此，这项研究具有重要的意义，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学过程的影响提供重要的机制见解。我们推测，DPP对于成牙本质细胞的存活、终末分化和有机基质的矿化是必不可少的。为了验证这一假说，我们建议使用分子方法：(A)研究DPP介导的黏附信号事件导致细胞增殖和存活的激活；(B)确定DPP激活Smad1及其下游转录反应导致成牙本质细胞终末分化的机制；(C)阐明DPP在调节羟基磷灰石成核和生长中的作用。从基质矿化和信号转导的角度理解DPP功能的进展在生物矿化领域具有广泛的意义。