CSF-1 in Dental Biology
CSF-1 在牙科生物学中的应用
基本信息
- 批准号:7663166
- 负责人:
- 金额:$ 28.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-03-05 至 2013-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAmeloblastsAmelogenesisAmelogenesis ImperfectaAnimal ModelBiologyCell LineageCell surfaceCellsComplementary DNADataDefectDentalDental EnamelDentinDevelopmentElectrophoretic Mobility Shift AssayEpithelialEpithelial CellsGene DeliveryGene ExpressionGenesGeneticGenetic CrossesGenetic TranscriptionGoalsHumanIn Situ HybridizationIn VitroIncisorKnock-outLacZ GenesLentivirus VectorLinkMacrophage Colony-Stimulating FactorMandibleMediatingMessenger RNAMolecularMorphologyMusNewborn InfantOdontoblastsOral healthOsteocalcinOsteoclastsPhenotypePlant RootsPrintingProtein IsoformsRegulatory ElementReporter GenesResolutionScanningSeriesTestingTherapeuticTimeTooth DiseasesTooth eruptionTooth structureTransfectionTransgenic MiceTransgenic OrganismsWorkbasecis acting elementenamel matrix proteinsenamelinfootgene therapyimprovedin vivokallikrein 4lentiviral-mediatedmineralizationmouse modelnovelnovel therapeuticspostnatalpreventpromoterprotein expressionpublic health relevanceresearch studyselective expressiontransgene expressionvector
项目摘要
DESCRIPTION (provided by applicant): Macrophage colony stimulating factor (CSF-1) is essential for tooth matrix formation and eruption. Ameloblasts and odontoblasts express soluble (s) and cell-surface (cs) forms of CSF-1; however, the precise biologic effects of these isoforms on amelogenesis and the regulatory elements in the CSF-1 gene that control their expression during tooth development have not been explored. The long-term goal of this proposal is to characterize the molecular mechanisms that control CSF- 1 expression in ameloblast lineage cells and determine the biologic effect of CSF-1 isoforms on enamel matrix formation using animal models. Our central working hypothesis is that CSF-1 is critical for amelogenesis during tooth development. Preliminary data show, for the first time, that a -774/+183 bp fragment of the CSF-1 promoter in transgenic mice confers high lacZ expression in the inner enamel epithelial (IEE) cells that differentiate into ameloblasts. Our first hypothesis is that cell-specific cis-acting elements in the -774 bp CSF-1 promoter direct gene expression in ameloblast lineage cells during tooth development. To address this issue, a series of -774 bp ]5'CSF-1 promoter deletion constructs will be tested for transcriptional activity in cultured ameloblast and non-ameloblast cells and relevant sequences will be analyzed in vivo by generating transgenic mice harboring these sequences linked to the lacZ reporter gene. In recent studies using op/op mice that lack both CSF-1 isoforms, we showed that absence of CSF-1 alters tooth matrix protein expression that, in turn, leads to enamel and dentin defects. Transgenic op/op mice expressing either csCSF-1 (op/opCS) or sCSF-1 (op/opS) in odontoblasts under the control of the osteocalcin (OC) promoter were generated and showed distinct tooth phenotypes. sCSF-1 corrected dentin and led to partial correction of enamel defects with op/opS mice showing unique features characterized by chalky white teeth and impaired root formation. These findings are novel and indicate that absence of CSF-1 in ameloblasts of op/opS teeth alters enamel matrix and root development. This is supported by our preliminary data in op/opS mice showing decreased enamelin and kallikrein-4 (KLK4, known as EMSP1) as well as shortened roots. Our second hypothesis is that CSF-1 isoforms differentially regulate enamel matrix and root formation and result in distinct phenotypes. For these experiments, the -774/+183 bp CSF-1 promoter will be used to selectively express sCSF-1 or csCSF-1 in ameloblasts. Double transgenic op/op mice carrying sCSF-1 under the OC promoter and harboring either sCSF-1 or csCSF-1 under the -774/+183 bp promoter will be established. Mice will be examined for resolution of enamel defects and teeth will be analyzed for morphology, enamel matrix protein expression, enamel integrity and mineralization. We will also test the hypothesis that lentiviral-mediated gene delivery of sCSF-1 to ameloblasts will rescue enamel/root defects in op/opS mice. Results from these studies should increase our understanding of the molecular mechanisms that regulate CSF-1 and identify distinct functional effects of sCSF-1 and csCSF-1 that may have therapeutic application for preventing enamel defects in acquired and genetic dental disorders such as amelogenesis imperfecta.
PUBLIC HEALTH RELEVANCE: Macrophage colony stimulating factor (CSF-1) is a key regulatory molecule for tooth matrix formation and eruption. Work in this proposal plans to determine the biologic effect of soluble and cell surface forms of CSF-1 on enamel matrix formation and the molecular mechanisms that control CSF-1 expression during tooth development using animal models and gene therapy approaches. Results from these studies may suggest novel therapeutic strategies for enhancing enamel integrity and improving oral health in acquired and genetic dental disorders.
说明(申请人提供):巨噬细胞集落刺激因子(CSF-1)是牙齿基质形成和萌出所必需的。成釉细胞和成牙本质细胞表达可溶性(S)和细胞表面(Cs)形式的csf-1;然而,这些异构体对成釉细胞发生的确切生物学作用以及csf-1基因中调控其在牙齿发育过程中表达的调控元件尚未被探索。这一建议的长期目标是通过动物模型表征控制成釉细胞系细胞中CSF-1表达的分子机制,并确定CSF-1亚型对牙釉质基质形成的生物效应。我们的中心工作假设是,在牙齿发育过程中,CSF-1在成釉过程中起关键作用。初步数据首次显示,在转基因小鼠中,CSF-1启动子的-774/+183bp片段在分化为成釉细胞的内釉上皮(IEE)细胞中高表达LacZ。我们的第一个假设是,在牙齿发育过程中,-774bpCSF-1启动子中的细胞特异性顺式作用元件直接在成釉细胞系细胞中进行基因表达。为了解决这个问题,我们将在培养的成釉细胞和非成釉细胞中测试一系列-774BP]5‘CSF-1启动子缺失构建体的转录活性,并通过产生携带这些序列的转基因小鼠来分析体内相关序列,这些序列与LacZ报告基因相连。在最近使用缺乏两种CSF-1亚型的OP/OP小鼠进行的研究中,我们发现缺乏CSF-1会改变牙齿基质蛋白的表达,进而导致牙釉质和牙本质缺陷。建立了在骨钙素(OC)启动子控制下在成牙本质细胞中表达csCSF-1(OP/OPC)或sCSF-1(OP/OP)的转基因OP/OP小鼠,并显示出不同的牙齿表型。SCSF-1纠正了牙本质,并导致OP/OPS小鼠部分修复了釉质缺陷,表现出白垩白牙齿和牙根形成障碍的独特特征。这些发现是新的,表明在OP/OP牙齿的成釉细胞中缺乏CSF-1会改变釉质基质和牙根发育。我们在OP/OPS小鼠中的初步数据支持了这一点,这些数据显示釉蛋白和激肽释放酶-4(KLK4,称为EMSP1)减少,根变短。我们的第二个假设是,CSF-1亚型不同地调节釉质基质和牙根的形成,并导致不同的表型。在这些实验中,-774/+183bpCSF-1启动子将被用于在成釉细胞中选择性地表达sCSF-1或csCSF-1。将建立在OC启动子下携带sCSF-1和在-774/+183 bp启动子下携带sCSF-1或csCSF-1的双转基因OP/OP小鼠。将检查小鼠牙釉质缺陷的解决情况,并分析牙齿的形态、牙釉质基质蛋白表达、牙釉质完整性和矿化情况。我们还将测试慢病毒介导的sCSF-1基因传递到成釉细胞将修复OP/OPS小鼠牙釉质/牙根缺陷的假设。这些研究的结果将增加我们对调节CSF-1的分子机制的理解,并确定sCSF-1和csCSF-1的不同功能效应,它们可能在预防获得性和遗传性牙病(如成釉发育不全)中的釉质缺陷方面具有治疗应用。
公共卫生相关性:巨噬细胞集落刺激因子(CSF-1)是牙齿基质形成和萌出的关键调节分子。这项建议的工作计划通过动物模型和基因治疗方法,确定可溶性和细胞表面形式的CSF-1对釉质基质形成的生物效应,以及在牙齿发育过程中控制CSF-1表达的分子机制。这些研究的结果可能会建议新的治疗策略,以增强釉质完整性和改善获得性和遗传性牙病的口腔健康。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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SHERRY L ABBOUD-WERNER其他文献
SHERRY L ABBOUD-WERNER的其他文献
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{{ truncateString('SHERRY L ABBOUD-WERNER', 18)}}的其他基金
CSF-1 Gene Expression in Osteoclast Biology
破骨细胞生物学中的 CSF-1 基因表达
- 批准号:
8631392 - 财政年份:2013
- 资助金额:
$ 28.13万 - 项目类别:
CSF-1 Gene Expression in Osteoclast Biology
破骨细胞生物学中的 CSF-1 基因表达
- 批准号:
8741919 - 财政年份:2013
- 资助金额:
$ 28.13万 - 项目类别:
CSF-1 Gene Expression in Osteoclast Biology
破骨细胞生物学中的 CSF-1 基因表达
- 批准号:
8885628 - 财政年份:2013
- 资助金额:
$ 28.13万 - 项目类别:
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