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

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.
项目概要 骨骼组织承受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 通过协调成骨细胞的形成,从整个骨基质的位置协调骨重塑 和破骨细胞吸收。骨细胞通过间隙与邻近的骨细胞和其他骨细胞连接 连接通道并通过半通道到达细胞外环境。两种类型的通道都是由 连接蛋白 (Cx) 43。Cx43 参与骨组织机械刺激的反应已被证实 在基因敲除模型中显示;然而,间隙连接通道和半通道的不同功能 骨细胞,以及这些通道在机械作用过程中生理作用的机制 装载仍然很大程度上未知。为了剖析这两类通道的生理作用,我们有 最近开发了两种主要表达 Cx43 显性失活突变体的转基因小鼠模型 在骨细胞中。我们还生成了 Cx43 突变基因敲入小鼠模型来补充我们的研究成果 转基因模型。这些突变损害骨细胞间隙连接通道和/或半通道。此外, 我们已经产生了特异性抑制 Cx43 半通道但不抑制间隙连接通道的抗体。 此外,我们还开发了新的方法,使我们能够原位评估骨细胞半通道活性。 初步数据表明,Cx43 半通道受损会减弱机械的合成代谢效应 负载在骨头上。我们和其他人还表明,骨细胞 Cx43 半通道是通过 机械应力,在体外释放包括前列腺素在内的小骨合成代谢因子。目标是 确定 Cx43 半通道在介导机械合成代谢效应中的具体机制作用 骨骼组织上的负荷。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发挥着至关重要的作用。 2) 检验骨细胞 Cx43 半通道介导机械负荷合成代谢功能的假设 通过 PGE2 释放以及 PGE2 和 Wnt 信号传导的激活。 3)检验激活和 Cx43 半通道的失活受到整合素激活/细胞骨架和 MAPK 的特异性调节 分别发出信号。拟议的研究预计将通过定义 骨组织中的机械传导机制及其调控,构成潜力,意义重大 为开发治疗骨质疏松症和骨的新治疗药物做出贡献 损失。

项目成果

期刊论文数量(0)
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Jean X Jiang其他文献

Jean X Jiang的其他文献

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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:
INTERCELLULAR COMMUNICATION IN THE EYE LENS
眼晶状体中的细胞间通讯
  • 批准号:
    6350874
  • 财政年份:
    1998
  • 资助金额:
    $ 33.55万
  • 项目类别:
INTERCELLULAR COMMUNICATION IN THE EYE LENS
眼晶状体中的细胞间通讯
  • 批准号:
    2872388
  • 财政年份:
    1998
  • 资助金额:
    $ 33.55万
  • 项目类别:

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