Skeletal Anabolism by Simultaneously Targeting the PTH1R and CaSR
同时靶向 PTH1R 和 CaSR 的骨骼合成代谢
基本信息
- 批准号:8834726
- 负责人:
- 金额:$ 3.79万
- 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:2014-12-01 至 2019-11-30
- 项目状态:已结题
- 来源:
- 关键词:1,25 (OH) vitamin DAddressAdultAdverse effectsAffectAgingAgonistAlveolar Bone LossAnabolismAnimal ModelBiochemicalBone InjuryBone ResorptionBone TissueBone necrosisCalciumCalcium-Sensing ReceptorsCell SurvivalCellsChronicCombined Modality TherapyDentalDenturesDeteriorationDevelopmentDiseaseDoseEconomicsEpidemicEstrogensFDA approvedFailureFellowshipFosteringFoundationsFractureGoalsGrowthHealedHealthHomeostasisHormonesHypercalcemiaHyperparathyroidismImplantIn VitroInjection of therapeutic agentIntestinesJawKidneyKnock-outLeadMandibleMandibular FracturesMethodsMolecularMorbidity - disease rateMusOncogenicOralOrganOsteoblastsOsteoclastsOsteogenesisOsteoporosisOutcomeParathyroid glandPatientsPredispositionReceptor GeneRegimenRiskSafetyScientistSerumSiteSkeletonStructureTestingTibial FracturesTimeTooth LossTrainingTreatment ProtocolsVertebral BoneWomanWorkbonebone lossbone massbone strengthbone turnovercareercraniofacialextracellularfallshealinghormone therapyimprovedinjury and repairloss of functionmenmouse modelnovelosteoblast differentiationosteoprogenitor cellosteosarcomaparathyroid hormone (1-34)pre-clinicalpreventpublic health relevancereceptor expressionrepairedresponseskeletalstem cellssubstantia spongiosa
项目摘要
DESCRIPTION (provided by applicant): Osteoporosis is a disease characterized by accelerated bone loss and deterioration of structural integrity of bone tissue, which lead to bone fracture susceptibility. This debilitating disease results when the rate of bone resorption by osteoclasts (OCLs) is greater than the rate of bone formation by osteoblasts (OBs). Current evidence shows that appendicular and vertebral bone as well as the craniofacial and oral bone structures are affected, resulting in reduced jawbone mass and periodontal bone loss, which complicates dental treatments. Intermittent parathyroid hormone (PTH) administration is the only FDA-approved therapy that produces bone anabolism and enhances bone injury repair. However, PTH dosing is limited to a short-term use with a relatively low dose due to its adverse hypercalcemic effects and oncogenic potential in bone. Therefore, a better understanding of the molecular and cellular mechanisms underlying the osteoanabolic actions and adverse effects of PTH is required to devise strategies to enhance PTH therapy. We hypothesize that the activation of the extracellular calcium-sensing receptors (CaSR) in the OB lineages are essential steps in producing osteoanabolic responses to intermittent PTH at appendicular and craniofacial sites and that combined treatment with a calcimimetic will enhance the osteoanabolic effects of intermittent PTH by simultaneously potentiating CaSR activities in OBs in normal and fracture bones. To test this hypothesis, a pharmacological approach will be taken to determine whether activating CaSRs in OBs by co-injecting the calcimimetic NPS-R568 enhances osteoanabolism of PTH in mouse models of aging and estrogen deficiency without producing hypercalcemia. This application aims to establish whether calcimimetics enhance anabolism of intermittent PTH by extending its anabolic window and/or by increasing its capacity to build bone. This will be achieved by assessing temporal changes in structural bone parameters, bone-forming and bone-resorbing rates histomorphometrically, numbers of stem cells in bone, and serum bone turnover markers. A loss-of- function approach using an OB-specific CaSR-KO mouse model with the combined regimens followed by biochemical and skeletal analysis will be taken to ascertain whether CaSR expression is required for (i) the growth, survival, and maturation of early OBs, and (ii) the mineralizing functions of mature OBs in the response of the cells to PTH and combined PTH/calcimimetic treatments. Using similar methods, it will be determined whether co-administration of NPS-R568 and PTH produces more robust healing of tibial and mandibular fractures than administration of PTH alone in adult mice. This work will reveal novel synergistic actions of intermittent PTH and Ca2+ in producing skeletal anabolism and establish preclinical regimens to restore osteoporotic skeleton and accelerate bone fracture repair.
描述(申请人提供):骨质疏松症是一种以骨丢失加速和骨组织结构完整性恶化为特征的疾病,导致骨折易感性。当破骨细胞(OCL)的骨吸收速率大于成骨细胞(OB)的骨形成速率时,会导致这种使人衰弱的疾病。目前的证据表明,颌骨和脊椎骨以及颅面和口腔骨结构受到影响,导致颌骨质量减少和牙周骨丢失,这使牙科治疗复杂化。间歇性甲状旁腺激素(PTH)给药是FDA批准的唯一一种产生骨愈合和增强骨损伤修复的治疗方法。然而,由于其不良的高钙作用和骨致癌潜力,PTH给药仅限于短期使用,剂量相对较低。因此,需要更好地了解PTH的骨合成代谢作用和不良反应的分子和细胞机制,以制定策略来加强PTH治疗。我们假设OB谱系中的细胞外钙敏感受体(CaSR)的激活是在approximular和颅面部位对间歇性PTH产生骨合成代谢反应的重要步骤,并且与拟钙剂联合治疗将通过同时增强正常骨和骨折骨中OB中的CaSR活性来增强间歇性PTH的骨合成代谢作用。为了检验这一假设,将采用药理学方法来确定通过共注射拟钙NPS-R568来激活OB中的CaSR是否在衰老和雌激素缺乏的小鼠模型中增强PTH的骨锚定而不产生高钙血症。本申请旨在确定拟钙剂是否通过延长其合成代谢窗口和/或通过增加其构建骨的能力来增强间歇性PTH的抑制。这将通过评估结构骨参数、骨形成和骨吸收率(组织形态计量学)、骨中干细胞数量和血清骨转换标志物的时间变化来实现。采用OB特异性CaSR-KO小鼠模型的功能丧失方法,采用联合方案,然后进行生化和骨骼分析,以确定CaSR表达是否是(i)早期OB的生长、存活和成熟所需,以及(ii)成熟OB在细胞对PTH和联合PTH/拟钙剂治疗的应答中的矿化功能所需。使用类似的方法,将确定在成年小鼠中NPS-R568和PTH的共同施用是否比单独施用PTH产生更稳健的胫骨和下颌骨骨折愈合。这项工作将揭示新的协同作用,间歇性PTH和钙离子在产生骨骼analgesia和建立临床前方案,以恢复骨质疏松的骨骼和加速骨折修复。
项目成果
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Christian Yuzon Santa Maria其他文献
Christian Yuzon Santa Maria的其他文献
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{{ truncateString('Christian Yuzon Santa Maria', 18)}}的其他基金
Skeletal Anabolism by Simultaneously Targeting the PTH1R and CaSR
同时靶向 PTH1R 和 CaSR 的骨骼合成代谢
- 批准号:
8951598 - 财政年份:2014
- 资助金额:
$ 3.79万 - 项目类别:
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