Connexin channels in transducing mechanical signals in bone
连接蛋白通道在骨中转导机械信号
基本信息
- 批准号:9754577
- 负责人:
- 金额:$ 33.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-01 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAntibodiesAttenuatedBiologicalBiomechanicsBlocking AntibodiesBone DiseasesBone MatrixBone ResorptionBone TissueBone remodelingCell SurvivalCellsCellular MechanotransductionComplementConnexin 43ConnexinsCytoskeletonDataDevelopmentDinoprostoneDominant-Negative MutationEnvironmentGap JunctionsGenesImpairmentIn SituIn VitroIntegrinsKnock-in MouseKnockout MiceLocationMAP Kinase GeneMechanical StimulationMechanical StressMechanicsMediatingMineralsModalityModelingMolecularMutationOsteocytesOsteogenesisOsteopeniaOsteoporosisOutcomePhenotypePhysiologicalPlayPropertyProstaglandinsRegulationResearchResearch ActivityRoleSignal TransductionTNFSF11 geneTestingTherapeuticTherapeutic AgentsTransgenic MiceTransgenic ModelWNT Signaling Pathwaybonebone cellbone losscell typedrug candidateexperienceextracellulargap junction channelin vivoknockout genemechanical loadmechanotransductionmouse modelmutantnew therapeutic targetnovelnovel strategiesnovel therapeuticsresponseskeletal tissuetreatment strategy
项目摘要
Project Summary
Mechanical loading experienced by skeletal tissues plays an important role in bone formation and remodeling.
Osteocytes are the most abundant bone cell type and the major mechanosensory cells of the bone. They
orchestrate bone remodeling from their location throughout bone matrix by coordinating osteoblastic formation
and osteoclastic resorption. Osteocytes are connected to neighboring osteocytes and other bone cells via gap
junction channels and to extracellular environments via hemichannels. Both types of channels are formed by
connexin (Cx) 43. The involvement of Cx43 in response to mechanical stimulation of bone tissue has been
shown in gene knockout models; however, the distinct functions of gap junction channels and hemichannels in
osteocytes, as well as the mechanism underlying the physiological roles of these channels during mechanical
loading remain largely unknown. To dissect the physiological roles of these two types of channels, we have
recently developed two transgenic mouse models expressing Cx43 dominant negative mutants predominantly
in osteocytes. We are also generating a Cx43 mutant gene knockin mouse model to complement our
transgenic models. These mutations impair osteocytic gap junction channels and/or hemichannels. In addition,
we have generated antibodies that specifically inhibit Cx43 hemichannels, but not gap junction channels.
Moreover, we have developed novel approaches that allow us to assess osteocytic hemichannel activity in situ.
Preliminary data show that impairment of Cx43 hemichannels attenuates the anabolic effect of mechanical
loading on the bone. We and others have also shown that osteocytic Cx43 hemichannels are opened by
mechanical stress, releasing small bone anabolic factors including prostaglandins in vitro. The objective is to
determine the specific mechanistic role of Cx43 hemichannels in mediating the anabolic effect of mechanical
loading on the skeletal tissues. Three specific aims are proposed: 1) To test the hypothesis that osteocytic
Cx43 hemichannels play a crucial role in mediating anabolic function of mechanical loading on skeletal tissue.
2) To test the hypothesis that osteocytic Cx43 hemichannels mediate anabolic function of mechanical loading
via PGE2 release, and activation of PGE2 and Wnt signaling. 3) To test the hypothesis that activation and
inactivation of Cx43 hemichannels are specifically regulated by integrin activation/cytoskeleton and MAPK
signaling, respectively. The proposed studies are expected to have a major positive impact by defining the
mechanical transduction mechanism and its regulation in bone tissue, constituting potential, significant
contributions toward the development of new therapeutic agents for the treatment of osteoporosis and bone
loss.
项目摘要
骨骼组织经历的机械负荷在骨形成和重塑中起着重要作用。
骨细胞是最丰富的骨细胞类型,也是骨骼的主要机械感觉细胞。他们
通过协调成骨细胞形成,从整个骨基质中策划骨头重塑
和整界碎屑吸收。骨细胞通过间隙连接到相邻的骨细胞和其他骨细胞
通过半通道的接线通道和细胞外环境。两种类型的渠道均由
连接蛋白(CX)43。响应于骨组织机械刺激的CX43的参与已是
在基因敲除模型中显示;但是,间隙连接通道和半通道的独特功能
骨细胞以及这些通道在机械过程中生理作用的机制
负载仍然很大未知。为了剖析这两种渠道的生理作用,我们有
最近开发了两个表达CX43显性阴性突变体的转基因小鼠模型
在骨细胞中。我们还生成CX43突变基因敲击蛋白小鼠模型以补充我们的
转基因模型。这些突变会损害骨细胞间隙连接通道和/或半通道。此外,
我们产生了专门抑制CX43半通道的抗体,但没有间隙连接通道。
此外,我们开发了新颖的方法,使我们能够原位评估骨细胞半通道活性。
初步数据表明,CX43半通道的损害会削弱机械的合成代谢效应
在骨头上加载。我们和其他人还表明,骨细胞CX43半通道由
机械应力,释放了包括前列腺素的小骨合成代谢因子。目的是
确定CX43半通道在介导机械效应中的特定机械作用
在骨骼组织上加载。提出了三个具体目标:1)检验骨细胞的假设
CX43半通道在介导骨骼组织机械负荷的合成代谢功能中起着至关重要的作用。
2)检验骨细胞CX43半通道介导机械负载的合成代谢功能的假设
通过PGE2释放以及PGE2和Wnt信号的激活。 3)检验激活和激活的假设
CX43半通道的灭活受整合素激活/细胞骨架和MAPK的特异性调节
信号分别。预计拟议的研究将通过定义
机械转导机制及其在骨组织中的调节,构成潜力,显着
为骨质疏松和骨骼治疗新的治疗剂开发的贡献
损失。
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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{{ truncateString('Jean X Jiang', 18)}}的其他基金
Proteoglycans and age-related deterioration of bone toughness
蛋白多糖与年龄相关的骨韧性退化
- 批准号:
10418752 - 财政年份:2019
- 资助金额:
$ 33.55万 - 项目类别:
Proteoglycans and age-related deterioration of bone toughness
蛋白多糖与年龄相关的骨韧性退化
- 批准号:
10186704 - 财政年份:2019
- 资助金额:
$ 33.55万 - 项目类别:
Proteoglycans and age-related deterioration of bone toughness
蛋白多糖与年龄相关的骨韧性退化
- 批准号:
10644016 - 财政年份:2019
- 资助金额:
$ 33.55万 - 项目类别:
Connexin channels in transducing mechanical signals in bone
连接蛋白通道在骨中转导机械信号
- 批准号:
10213655 - 财政年份:2018
- 资助金额:
$ 33.55万 - 项目类别:
Connexin channels in transducing mechanical signals in bone
连接蛋白通道在骨中转导机械信号
- 批准号:
10447057 - 财政年份:2018
- 资助金额:
$ 33.55万 - 项目类别:
Connexin hemichannels in suppression of breast cancer bone metastasis
连接蛋白半通道抑制乳腺癌骨转移
- 批准号:
9030104 - 财政年份:2016
- 资助金额:
$ 33.55万 - 项目类别:
Role of mechanical strain in GAP junctions in osteocytes
机械应变在骨细胞间隙连接中的作用
- 批准号:
6583191 - 财政年份:2002
- 资助金额:
$ 33.55万 - 项目类别:
Role of mechanical strain in GAP junctions in osteocytes
机械应变在骨细胞间隙连接中的作用
- 批准号:
6663349 - 财政年份:2002
- 资助金额:
$ 33.55万 - 项目类别:
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