Calcium Regulation in Osteoclasts
破骨细胞中的钙调节
基本信息
- 批准号:8913682
- 负责人:
- 金额:$ 41.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-17 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAmino AcidsAnimal ModelAnimalsAutomobile DrivingBindingBiochemicalBiologicalBone MarrowBone ResorptionBone remodelingCalciumCell ProliferationCell Surface ReceptorsCellsCoculture TechniquesComplexCritical PathwaysCytokine SignalingCytoplasmic ProteinDataDefectDevelopmentDietDiseaseEquilibriumEventFrequenciesGenesHealthHematopoietic stem cellsIn VitroInositolIon ChannelKnock-outKnockout MiceLeadLifeMacrophage Colony-Stimulating FactorMediatingMolecularMusMyelogenousNeoplasm MetastasisNuclearObstructionOsteoblastsOsteoclastsOsteogenesisOsteoporosisOvariectomyPaget&aposs DiseasePathway interactionsPeriodontitisPhenotypeProcessProtein BindingProtein IsoformsProteinsRNA SplicingRecruitment ActivityRegulationRheumatoid ArthritisRoleSeriesSignal TransductionStagingStromal CellsTNFSF11 geneTestingTherapeuticUp-RegulationVariantWorkbasebiophysical techniquesbonebone lossdesignimprovedin vivoinhibitor/antagonistnovel therapeutic interventionosteoclastogenesispreventprogenitorprogramsreceptorreceptor couplingresearch studyresponsestoichiometry
项目摘要
DESCRIPTION (provided by applicant): Healthy bone maintains a balance of bone formation mediated by osteoblasts and bone resorption mediated by osteoclasts. Many disease states, including chronic periodontitis, osteoporosis, rheumatoid arthritis, Paget's disease, and cancer metastases develop when osteoclasts are excessively recruited or inappropriately activated. Osteoclasts are constantly made throughout life from hematopoietic stem cells residing in the bone marrow through a series of complex events involving cytokine signaling and the microenvironment. Ca2+ signaling has an essential role in the regulation of osteoclastogenesis. Ca2+ channels activated in response to the depletion of intracellular Ca2+ stores have been suggested to mediate Ca2+ signaling in early stages of osteoclast formation. However, the exact molecules and the mechanism by which these channels control Ca2+ signaling in osteoclastogenesis are largely unknown. Using a combination of molecular, cell biological and whole animal studies, we show that the Transient Receptor Potential channel, TRPC1, enhances osteoclastogenesis at an early stage, whereas its inhibitor, the small cytosolic protein, I-mfa has an opposite effect. Enhanced osteoclastogenesis in I-mfa-null mice is corrected in mice lacking both genes indicating that TRPC1-mediated Ca2+ signaling has a dominant effect over I-mfa in osteoclast formation. Therefore, we propose that TRPC1 and I-mfa are essential for osteoclastogenesis by regulating Ca2+ signaling. This hypothesis will be tested by an integrated approach at the molecular, biophysical, cellular, and organismal levels by asking whether and how TRPC1 and I-mfa affect proliferation and "priming" of early osteoclast progenitors (Specific Aim 1), how TRPC1 and I-mfa modulate Ca2+ signaling in osteoclasts (Specific Aims 2 and 3), and whether TRPC1 and I-mfa affect osteoclastogenesis in a cell-autonomous fashion in vivo and in vitro and further, whether they affect osteoclast recruitment in experimentally induced animal models of osteoclastogenesis (Specific Aim 4). Our studies will lead to further understanding of critical pathways in the regulation of osteoclast development and function, which is needed to identify and develop new therapeutic interventions to control osteoclastogenesis and prevent bone loss.
描述(由申请人提供):健康的骨骼维持由成骨细胞介导的骨形成和由破骨细胞介导的骨吸收的平衡。许多疾病状态,包括慢性牙周炎、骨质疏松症、类风湿性关节炎、佩吉特氏病和癌症转移,都是在破骨细胞过度募集或不适当激活时发生的。破骨细胞是在整个生命过程中,通过一系列涉及细胞因子信号传导和微环境的复杂事件,由骨髓中的造血干细胞不断产生的。 Ca2+ 信号传导在破骨细胞生成的调节中具有重要作用。响应细胞内 Ca2+ 储备耗尽而激活的 Ca2+ 通道被认为可以在破骨细胞形成的早期阶段介导 Ca2+ 信号传导。然而,这些通道在破骨细胞生成过程中控制 Ca2+ 信号传导的确切分子和机制尚不清楚。通过结合分子、细胞生物学和整体动物研究,我们发现瞬时受体电位通道 TRPC1 可在早期增强破骨细胞生成,而其抑制剂、小胞质蛋白 I-mfa 则具有相反的作用。 I-mfa缺失小鼠中增强的破骨细胞生成在缺乏这两种基因的小鼠中得到纠正,表明TRPC1介导的Ca2+信号在破骨细胞形成中比I-mfa具有主导作用。因此,我们认为 TRPC1 和 I-mfa 通过调节 Ca2+ 信号传导对于破骨细胞生成至关重要。该假设将通过分子、生物物理、细胞和有机体水平的综合方法进行测试,询问 TRPC1 和 I-mfa 是否以及如何影响早期破骨细胞祖细胞的增殖和“启动”(具体目标 1),TRPC1 和 I-mfa 如何调节破骨细胞中的 Ca2+ 信号传导(具体目标 2 和 3),以及 TRPC1 和 I-mfa 是否 在体内和体外以细胞自主方式影响破骨细胞生成,此外,它们是否影响实验诱导的破骨细胞生成动物模型中的破骨细胞募集(具体目标 4)。我们的研究将进一步了解破骨细胞发育和功能调节的关键途径,这是确定和开发新的治疗干预措施以控制破骨细胞生成和防止骨质流失所必需的。
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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Mary Beth Humphrey其他文献
735 - Vagal Nerve Stimulation Mitigates Pain in Mouse Models of Post-Traumatic Osteoarthritis
- DOI:
10.1016/j.joca.2024.02.750 - 发表时间:
2024-04-01 - 期刊:
- 影响因子:
- 作者:
Mary Beth Humphrey;Shivmurat Yadav;Monika Niewiadomska;Lynsie Morris;Taylor Connor;Jessica Lumry;Sanique South;Emmaline Prinz;Stavros Stavrakis;Matlock Jeffries;Timothy Griffin - 通讯作者:
Timothy Griffin
Exercise induces dynamic changes in intra-articular metabolism and inflammation associated with remodeling of the infrapatellar fat pad in mice
运动可引起小鼠髌下脂肪垫重塑相关的关节内代谢和炎症的动态变化
- DOI:
10.1038/s41598-025-86726-0 - 发表时间:
2025-01-18 - 期刊:
- 影响因子:3.900
- 作者:
Timothy M. Griffin;Ravi K. Komaravolu;Erika Barboza Prado Lopes;Padmaja Mehta-D’souza;Taylor Conner;Tessa Kovats;Susan Kovats;Madeline Allen;Peyton Harris;Mary Beth Humphrey;Hope D. Welhaven;Priyanka Brahmachary;Ronald K. June - 通讯作者:
Ronald K. June
Current Treatment for Glucocorticoid-Induced Osteoporosis: Beyond Bisphosphonates
- DOI:
10.1007/s40674-024-00219-1 - 发表时间:
2024-10-04 - 期刊:
- 影响因子:1.300
- 作者:
Mary Beth Humphrey - 通讯作者:
Mary Beth Humphrey
Mary Beth Humphrey的其他文献
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{{ truncateString('Mary Beth Humphrey', 18)}}的其他基金
BCCMA: Targeting Osteoarthritis Pain and Progression: Preclinical OA models of vagal nerve stimulation to reduce pain and progression of OA
BCCMA:针对骨关节炎疼痛和进展:通过刺激迷走神经来减轻骨关节炎疼痛和进展的临床前 OA 模型
- 批准号:
10485419 - 财政年份:2022
- 资助金额:
$ 41.1万 - 项目类别:
UNDERSTANDING THE ROLE OF ALTERNATIVE SPLICING IN THE TNFAIP3 SLE-RISK ALLELES
了解选择性剪接在 TNFAIP3 SLE 风险等位基因中的作用
- 批准号:
8359795 - 财政年份:2011
- 资助金额:
$ 41.1万 - 项目类别:
UNDERSTANDING THE ROLE OF ALTERNATIVE SPLICING IN THE TNFAIP3 SLE-RISK ALLELES
了解选择性剪接在 TNFAIP3 SLE 风险等位基因中的作用
- 批准号:
8168263 - 财政年份:2010
- 资助金额:
$ 41.1万 - 项目类别:
SHIP1 REGULATION OF DAP12 IN OSTEOCLAST DEVELOPMENT AND FUNCTION
SHIP1 对 DAP12 对破骨细胞发育和功能的调节
- 批准号:
7960579 - 财政年份:2009
- 资助金额:
$ 41.1万 - 项目类别:
Mechanism of ITAM Signal Regulation in Osteoclasts
破骨细胞ITAM信号调控机制
- 批准号:
8305426 - 财政年份:2008
- 资助金额:
$ 41.1万 - 项目类别:
Mechanism of ITAM Signal Regulation in Osteoclasts
破骨细胞ITAM信号调控机制
- 批准号:
7906881 - 财政年份:2008
- 资助金额:
$ 41.1万 - 项目类别:
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