Function of Regulator of G protein signaling in aging skeleton
G蛋白信号调节因子在骨骼衰老中的作用
基本信息
- 批准号:9294321
- 负责人:
- 金额:$ 36.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-08-01 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAffectAgeAge-Related Bone LossAge-Related OsteoporosisAgingBindingBiological AssayBone DiseasesBone ResorptionBone remodelingCalcium ChannelCalcium SignalingCalcium-Sensing ReceptorsCell LineageDataDiseaseEctopic ExpressionFamilyFc ReceptorFractureGTP-Binding Protein RegulatorsGoalsGuanosine Triphosphate PhosphohydrolasesHealthHematopoieticHeterodimerizationHeterogeneityImmunoprecipitationIn VitroKnockout MiceLigandsMarrowMass Spectrum AnalysisMediatingMesenchymalMolecularMusNuclearOsteoclastsOsteoporosisPTB DomainPTH genePathologicPathway interactionsPatientsPhenotypePhosphorylationPhosphotyrosinePlayProteinsPublic HealthRGS DomainRGS ProteinsRGS1 geneRegulationResearchRoleSelective Estrogen Receptor ModulatorsSeriesSkeletonSpecificityTNFSF11 geneTestingTherapeutic InterventionWomanagedbasebisphosphonatebonebone massbone metabolismcathepsin Kinsightknock-downlipid biosynthesismenmutantnuclear factors of activated T-cellsosteoclastogenesisphospholipase C gammapostnatalreceptorresponseskeletaltherapeutic target
项目摘要
DESCRIPTION (provided by applicant): Age-associated osteoporosis is a major health problem, which is characterized by an imbalance in bone remodeling and metabolism due to the increase of osteoclastogenesis and activity with age. The current treatment options have been constrained with lower response rates or side-effects and ineffectively tackle the burden and heterogeneity of osteoporosis. Further progress in establishing successful treatment urgently requires a clearer understanding of the mechanisms of osteoclast (OC) differentiation and bone remodeling with age. Evidences have documented that RANKL -evoked Ca2+ oscillations play a switch-on role in the activation of PLC� and NFATc1, and OC differentiation. Further study showed that FcR� and DAP 12 regulate the phosphorylation of PLC�, which is the critical component involved in the RANKL-induced Ca2+ oscillations- NFATc1 pathway. Despite these new insights, it remains unclear how RANKL evokes the essential Ca2+ oscillations that triggers NFATc1 activation and OC differentiation, and it is unknown whether and how this mechanism is involved in age-associated bone loss. Our recent research demonstrated that Regulator of G protein signaling protein 12 (RGS12) was prominently expressed during OC differentiation and that RGS12 expression was significantly increased with increasing age. Knockdown of RGS12 expression inhibited Ca2+ oscillations, NFATc1 expression and OC differentiation. Deletion of RGS12 from hematopoietic/early OC lineage cells (RGS12 / /cre) led to a significantly increase of bone mass, and this increase of bone mass was protected from age-associated bone loss in RGS12 / /cre mice. We also found that loss of RGS12 in mice decreased OC number and levels of marrow adipogenesis with age. Based on these results, we hypothesize that age-associated bone remodeling and metabolism requires RGS12 expression and function, and RGS12 is a critical regulator in controlling Ca2+ oscillation and OC differentiation during aging. We will test the hypothesis through the following two specific aims. In Aim 1, we will reveal the function of RGS12 in OC differentiation and function during aging through characterization of the phenotypes and pathomechanism of RGS12 conditional knockout mice. We will analyze bone phenotypes in young (6 months (m)), mid-aged (14m) and aged (24m) mice to determine how deletion of RGS12 in early and late OC lineage cells affect postnatal age-associated bone metabolism by using Mx1-cre and Cathepsin K-Cre mice. We will further characterize in vitro of OCs derived from aging RGS12 / /cre mice and determine the contribution of mesenchymal lineage cells to the OCs and skeletal phenotype in aging RGS12 / /cre mice. In Aim 2, we will elucidate the mechanism of RGS12 interactions that confer specificity of Ca2+ oscillation and OCs with age by characterizing pathomechanism and pathways, RGS12 domain functions and its heterodimerization partners. The goal of this project is to discover the role and mechanism of RGS12 in OC differentiation and activation in pathologic age condition, and provide new and more effective therapeutic targets to age-associated osteoporosis and other bone diseases.
描述(由适用提供):与年龄相关的骨质疏松症是一个主要的健康问题,其特征是骨重塑和代谢因骨质栓塞的增加和随着年龄的增长而导致活性。当前的治疗选择受到较低的反应率或副作用的限制,并无效地应对骨质疏松症的负担和异质性。在急切地建立成功治疗方面的进一步进展需要更清楚地了解破骨细胞(OC)分化和随着年龄的重塑的机制。有证据表明,RANKL引起的Ca2+振荡在PLC和NFATC1的激活中起着切换的作用,以及OC分化。进一步的研究表明,FCR和DAP 12调节PLC的磷酸化,这是RANKL诱导的Ca2+振荡 - NFATC1途径所涉及的关键成分。尽管有这些新的见解,但尚不清楚Rankl如何唤起触发NFATC1激活和OC分化的必需CA2+振荡,并且未知该机制是否以及如何参与与年龄相关的骨骼流失有关。我们最近的研究表明,G蛋白信号蛋白12(RGS12)的调节剂在OC分化过程中显着表达,并且随着年龄的增长,RGS12表达显着增加。 RGS12表达的敲低抑制了Ca2+振荡,NFATC1表达和OC分化。从造血 /早期OC谱系细胞(RGS12 / /CRE)中删除RGS12导致骨骼质量显着增加,并且骨骼质量的增加受到RGS12 / /CRE小鼠的年龄相关骨损失的保护。我们还发现,小鼠RGS12的损失随着年龄的增长而降低了骨髓脂肪形成的水平。基于这些结果,我们假设与年龄相关的骨骼重塑和代谢需要RGS12的表达和功能,而RGS12是控制Ca2+振荡和OC分化过程中的关键调节剂。我们将通过以下两个具体目标来检验假设。在AIM 1中,我们将通过表征RGS12条件基因敲除小鼠的表征和病原机制来揭示RGS12在OC分化和功能中的功能。我们将分析年轻(6个月(M)),中年(14m)和年龄(24m)小鼠的骨骼表型,以确定使用MX1-CRE和CATAREPSIN K-CRE小鼠使用MX1-CRE和CATAREPSIN K-CRE小鼠来确定早期和晚期OC谱系细胞中RGS12的缺失如何影响与年龄相关的骨代谢。我们将进一步表征源自衰老RGS12 / / CRE小鼠的OC的体外,并确定间充质谱系细胞对OCS的贡献和在衰老的RGS12 / / CRE小鼠中的骨骼表型。在AIM 2中,我们将阐明RGS12相互作用的机制,即通过表征病理力学和途径,RGS12域功能及其异二聚化伴侣,通过表征病理机制和途径,将Ca2+振荡和OC与年龄的年龄进行了特异性。该项目的目的是发现RGS12在病理年龄条件下的OC分化和激活中的作用和机制,并为年龄相关的骨质疏松症和其他骨骼疾病提供新的,更有效的治疗靶标。
项目成果
期刊论文数量(0)
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SHUYING YANG其他文献
SHUYING YANG的其他文献
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{{ truncateString('SHUYING YANG', 18)}}的其他基金
Regulation of skeletal development and homeostasis by IFT protein
IFT 蛋白对骨骼发育和稳态的调节
- 批准号:
9292979 - 财政年份:2016
- 资助金额:
$ 36.79万 - 项目类别:
Role of RGS12, a Regulator of G protein Signaling, in Bone Remodeling
RGS12(G 蛋白信号传导调节剂)在骨重塑中的作用
- 批准号:
9294325 - 财政年份:2016
- 资助金额:
$ 36.79万 - 项目类别:
Regulation of skeletal development and homeostasis by IFT protein
IFT 蛋白对骨骼发育和稳态的调节
- 批准号:
9271951 - 财政年份:2016
- 资助金额:
$ 36.79万 - 项目类别:
Function of Regulator of G protein signaling in aging skeleton
G蛋白信号调节因子在骨骼衰老中的作用
- 批准号:
8767760 - 财政年份:2014
- 资助金额:
$ 36.79万 - 项目类别:
Regulation of skeletal development and homeostasis by IFT protein
IFT 蛋白对骨骼发育和稳态的调节
- 批准号:
8697956 - 财政年份:2014
- 资助金额:
$ 36.79万 - 项目类别:
Function of Regulator of G protein signaling in aging skeleton
G蛋白信号调节因子在骨骼衰老中的作用
- 批准号:
9346657 - 财政年份:2014
- 资助金额:
$ 36.79万 - 项目类别:
Role of RGS12, a Regulator of G protein Signaling, in Bone Remodeling
RGS12(G 蛋白信号传导调节剂)在骨重塑中的作用
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8842593 - 财政年份:2014
- 资助金额:
$ 36.79万 - 项目类别:
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