Assessing the function role of sclerostin in periodontal disease in XLH
评估硬化素在 XLH 牙周病中的功能作用
基本信息
- 批准号:10303753
- 负责人:
- 金额:$ 16.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAlveolarAntibodiesAntibody TherapyAreaAutomobile DrivingBiologyCell Differentiation processCellsCementocyteClinicalCollaborationsComplexDataDefectDentalDental CementumDental PulpDental SacDentinDevelopmentDiseaseEndopeptidasesEventExperimental ModelsFDA approvedFamilial hypophosphatemic bone diseaseFoundationsFunctional disorderFundingFutureGenesGeneticGoalsHeritabilityHigh PrevalenceHormonesHypophosphatemiaImpairmentIndividualKidneyLaboratoriesMeasuresMediator of activation proteinMineralsMusMutationOsteocytesOsteogenesisOutcomePathologyPatientsPeriodontal DiseasesPeriodontal LigamentPeriodontitisPeriodontiumPharmacologic SubstancePharmacologyPhysiologic calcificationPlant RootsProcessProductionProteinsPublishingReportingResearchRicketsRoleSignal TransductionSkeletonStructureSymptomsTestingTherapeuticThickTimeTissuesTooth DiseasesTooth structureTrainingWNT Signaling PathwayWorkX Chromosomealveolar bonebonebone masscraniofacialfibroblast growth factor 23fracture riskgain of function mutationgenetic approachhigh riskimprovedimproved outcomeinorganic phosphateloss of functionloss of function mutationmineralizationmouse modelneutralizing antibodynovelosteogenicpreventskeletalstem cellstreatment strategywasting
项目摘要
Project Summary
X-linked hypophosphatemia (XLH) is the most common form of heritable Rickets, characterized clinically by
impaired skeletal mineralization and low circulating phosphate levels. XLH is caused by a mutation in the
phosphate regulating gene with homology to endopeptidase located on the X chromosome (PHEX) gene,
which leads to elevated levels of the phosphotropic hormone, fibroblast growth factor 23 (FGF23), and
subsequently renal phosphate wasting. XLH patients also present with a variety of periodontal defects,
including aberrant mineralization of both the alveolar bone and cementum, as well as poor periodontal ligament
attachment. Although novel treatment strategies have been developed that block FGF23 activity and increase
phosphate levels, periodontal disease remains a clinical concern. Our laboratory has recently demonstrated
that sclerostin antibody treatment reduces FGF23 and increases circulating phosphate levels. These systemic
changes were associated with increased bone mass and mineralization levels in the axial skeleton of Hyp
mice. In the current proposal we propose to test the hypothesis that sclerostin is an important mediator of XLH-
related periodontal disease and that suppression of sclerostin activity will improve periodontitis. This
hypothesis is built on published reports describing the importance of sclerostin and Wnt-signaling in the
development of mineralized tissues, including the periodontium. Further, our preliminary data has
demonstrated that sclerostin antibody treatment improves alveolar bone mass and periodontal ligament
attachment in Hyp mice. To test our hypothesis, we will analyze whether suppressing sclerostin activity via
both genetic and pharmaceutical strategies improves the periodontal defects in Hyp mice (Aim 1) and
determine the role of sclerostin in the osteogenic differentiation of dental follicle progenitor cells (DFPCs, Aim
2). If successful, the current proposal will further our understanding of the pathophysiology of periodontitis in
XLH and provide translational data on the use of a sclerostin antibody, a recently FDA-approved
pharmaceutical treatment. Further, the proposal will serve to build the expertise and preliminary data
necessary for Dr. Ross to compete for future R01-level funding in dental and craniofacial research.
项目概要
X连锁低磷血症(XLH)是遗传性佝偻病最常见的形式,临床特征为
骨骼矿化受损和循环磷酸盐水平低。 XLH是由基因突变引起的
与位于X染色体上的内肽酶同源的磷酸调节基因(PHEX)基因,
这会导致促磷酸激素、成纤维细胞生长因子 23 (FGF23) 和
随后肾磷酸盐消耗。 XLH患者还存在多种牙周缺陷,
包括牙槽骨和牙骨质的异常矿化,以及牙周膜的不良
依恋。尽管已经开发出新的治疗策略来阻断 FGF23 活性并增加
磷酸盐水平,牙周病仍然是临床关注的问题。我们的实验室最近证明
硬化蛋白抗体治疗可减少 FGF23 并增加循环磷酸盐水平。这些系统性的
变化与 Hyp 中轴骨骼的骨量和矿化水平增加有关
老鼠。在当前的提案中,我们建议检验以下假设:硬化素是 XLH- 的重要介质。
相关的牙周病,并且抑制硬化蛋白活性将改善牙周炎。这
假设是建立在已发表的报告的基础上的,这些报告描述了硬化蛋白和 Wnt 信号传导在
矿化组织的发育,包括牙周组织。此外,我们的初步数据有
证明硬化素抗体治疗可改善牙槽骨质量和牙周膜
Hyp 小鼠的附着。为了检验我们的假设,我们将分析是否通过抑制硬化素活性
遗传和药物策略均可改善 Hyp 小鼠的牙周缺陷(目标 1)
确定硬化素在牙囊祖细胞(DFPCs,Aim
2)。如果成功,当前的提议将进一步加深我们对牙周炎病理生理学的理解
XLH 并提供有关使用 sclerostin 抗体(最近 FDA 批准的一种药物)的转化数据
药物治疗。此外,该提案将有助于建立专业知识和初步数据
这对于 Ross 博士竞争未来牙科和颅面研究领域的 R01 级资金来说是必要的。
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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Ryan Dee Ross其他文献
Ryan Dee Ross的其他文献
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{{ truncateString('Ryan Dee Ross', 18)}}的其他基金
Identifying the long-term metabolic complications of in-utero and lactational antiretroviral exposure
确定子宫内和哺乳期抗逆转录病毒暴露的长期代谢并发症
- 批准号:
10762179 - 财政年份:2023
- 资助金额:
$ 16.75万 - 项目类别:
Bone and fat cross-talk in antiretroviral therapy (ART) treated HIV patients
抗逆转录病毒疗法 (ART) 治疗的 HIV 患者的骨和脂肪交叉对话
- 批准号:
10548410 - 财政年份:2022
- 资助金额:
$ 16.75万 - 项目类别:
Bone and fat cross-talk in antiretroviral therapy (ART) treated HIV patients
抗逆转录病毒疗法 (ART) 治疗的 HIV 患者的骨和脂肪交叉对话
- 批准号:
10856307 - 财政年份:2022
- 资助金额:
$ 16.75万 - 项目类别:
Characterization of a humanized mouse model to study HIV and ARV effects on bone
研究 HIV 和 ARV 对骨骼影响的人源化小鼠模型的表征
- 批准号:
10324198 - 财政年份:2021
- 资助金额:
$ 16.75万 - 项目类别:
Assessing the function role of sclerostin in periodontal disease in XLH
评估硬化素在 XLH 牙周病中的功能作用
- 批准号:
10454382 - 财政年份:2021
- 资助金额:
$ 16.75万 - 项目类别:
Sclerostin Regulation of Skeletal Mineralization and Phosphate Metabolism
硬化素对骨骼矿化和磷酸盐代谢的调节
- 批准号:
10457434 - 财政年份:2019
- 资助金额:
$ 16.75万 - 项目类别:
Sclerostin Regulation of Skeletal Mineralization and Phosphate Metabolism
硬化素对骨骼矿化和磷酸盐代谢的调节
- 批准号:
10240577 - 财政年份:2019
- 资助金额:
$ 16.75万 - 项目类别:
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