Modifying the mechanotransduction of bone by targeting purinergic receptors

通过靶向嘌呤能受体来改变骨的机械传导

基本信息

  • 批准号:
    10680508
  • 负责人:
  • 金额:
    $ 33.11万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-01 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

Osteoporotic fractures are common, increasing in incidence, and have a high associated economic burden. This significant clinical problem is further compounded by a lack of therapeutic strategies to increase bone formation and improve tissue strength. Bone formation is a function of osteocytes’ response to mechanical loading during physical activity and exercise. Osteocytes’ purinergic signaling through the release of nucleotides plays a key role in regulating bone adaptation in response to loading. In particular we have found the P2Y2 receptor downregulates osteocytes’ sensitivity to loading and that the loss in mechanosensitivity is accompanied by an increase in actin-stress fiber formation (ASFF) through cofilin phosphorylation. These findings are significant because they suggest targeting P2Y2 signaling as a potential strategy to enhance osteocyte mechanotransduction and increase bone formation. However, the extent to which P2Y2 influences bone formation by regulating osteocytes’ sensitivity to loading through ASFF remains unknown. These gaps in knowledge limit our development of new therapeutic strategies that increase bone formation and reduce fracture risk in an aging population. Our long-term goal is to prevent osteoporosis and reduce fracture risk in an aging population. The objective of this study is to determine the role of purinergic signaling through the P2Y2 receptor in regulating the anabolic response to loading. The premise for this study is that blocking P2Y2 signaling has therapeutic potential to prevent age-related bone loss and reduce fracture risk. The central hypothesis states that blocking P2Y2 signaling will increase osteocytes’ sensitivity to loading, allowing greater gains in bone mass and tissue strength in response to loading. The central hypothesis will be tested under three specific aims. Aim 1 will determine the extent to which P2Y2 signaling in-vitro influences osteocytes’ sensitivity and overall response to loading by regulating ASFF through cofilin phosphorylation. Our approach in aim 1 utilizes osteocyte knockout cell lines generated using CRISPR/Cas9 to examine in-vitro their response to fluid flow. Aim 2 will determine the extent to which P2Y2 expression in-vivo contributes to bone formation in response to loading and unloading. Our approach in aim 2 will prescribe treadmill exercise and hindlimb immobilization to conditional knockout mice that target osteocytes’ P2Y2 expression. Aim 3 will examine the efficacy of AR-C118925, a selective P2Y2R inhibitor, to increase the anabolic response to loading in aged mice as well as prevent age-related bone loss. Our approach in aim 3 will treat wild-type as well as P2Y2- knockout mice with AR-C118925 to identify off-target effects that are not specific to osteocytes. This study is innovative because it 1) evaluates a novel therapeutic agent (AR-C118925) for increasing bone formation, and 2) uses new cell-lines and animal models to establish P2Y2 signaling as a unique mechanism to increase bone mass. Overall, this study is significant because we expect it to demonstrate the therapeutic potential of targeting P2Y2R signaling to increase bone formation and reduce fracture risk.
骨质疏松性骨折很常见,发病率不断增加,并且具有很高的相关经济负担。 由于缺乏增加骨量的治疗策略,这一重大的临床问题进一步复杂化。 形成并提高组织强度。骨形成是骨细胞对机械反应的函数 体力活动和锻炼期间的负荷。骨细胞通过释放嘌呤能信号 核苷酸在调节骨响应负荷的适应中起着关键作用。特别是我们发现 P2Y2 受体下调骨细胞对负载的敏感性,并且机械敏感性的损失 伴随着肌丝蛋白丝切蛋白磷酸化导致的肌动蛋白应力纤维形成(ASFF)的增加。这些 研究结果意义重大,因为它们表明以 P2Y2 信号为目标的潜在策略是增强 骨细胞机械传导并增加骨形成。然而,P2Y2 的影响程度 通过 ASFF 调节骨细胞对负荷的敏感性来形成骨仍然未知。这些差距 知识限制了我们开发新的治疗策略,以增加骨形成并减少 人口老龄化带来的骨折风险。我们的长期目标是预防骨质疏松症并降低骨折风险 人口老龄化。本研究的目的是确定嘌呤能信号通过 P2Y2 的作用 受体调节对负荷的合成代谢反应。本研究的前提是阻断 P2Y2 信号传导具有预防与年龄相关的骨质流失和降低骨折风险的治疗潜力。中央 假设指出,阻断 P2Y2 信号传导将增加骨细胞对负载的敏感性,从而允许更大的 骨量和组织强度因负荷而增加。中心假设将在以下条件下进行检验 三个具体目标。目标 1 将确定 P2Y2 信号传导体外影响骨细胞的程度 通过丝切蛋白磷酸化调节 ASFF 对负荷的敏感性和总体反应。我们的方法 目标 1 利用 CRISPR/Cas9 生成的骨细胞敲除细胞系来检查它们对 流体流动。目标 2 将确定体内 P2Y2 表达对骨形成的贡献程度 对装载和卸载的响应。我们在目标 2 中的方法将规定跑步机锻炼和后肢锻炼 固定到针对骨细胞 P2Y2 表达的条件敲除小鼠中。目标 3 将检查 AR-C118925(一种选择性 P2Y2R 抑制剂)在增加老年人对负荷的合成代谢反应方面的功效 小鼠还可以预防与年龄相关的骨质流失。我们在目标 3 中的方法将治疗野生型以及 P2Y2- 使用 AR-C118925 敲除小鼠,以识别非骨细胞特有的脱靶效应。这项研究是 创新是因为它 1) 评估了一种用于增加骨形成的新型治疗剂 (AR-C118925),以及 2) 使用新的细胞系和动物模型建立 P2Y2 信号传导作为增加骨质的独特机制 大量的。总的来说,这项研究意义重大,因为我们希望它能够证明其治疗潜力 靶向 P2Y2R 信号传导以增加骨形成并降低骨折风险。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Diminishing Returns of Mechanical Loading and Potential Mechanisms that Desensitize Osteocytes.
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Joseph Daniel Gardinier其他文献

Joseph Daniel Gardinier的其他文献

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{{ truncateString('Joseph Daniel Gardinier', 18)}}的其他基金

Modifying the mechanotransduction of bone by targeting purinergic receptors
通过靶向嘌呤能受体来改变骨的机械传导
  • 批准号:
    10242712
  • 财政年份:
    2020
  • 资助金额:
    $ 33.11万
  • 项目类别:
Modifying the mechanotransduction of bone by targeting purinergic receptors
通过靶向嘌呤能受体来改变骨的机械传导
  • 批准号:
    10470176
  • 财政年份:
    2020
  • 资助金额:
    $ 33.11万
  • 项目类别:
The Influence of PTH during Exercise on Bone Quality
运动时PTH对骨质量的影响
  • 批准号:
    8525721
  • 财政年份:
    2013
  • 资助金额:
    $ 33.11万
  • 项目类别:
The Influence of PTH during Exercise on Bone Quality
运动时PTH对骨质量的影响
  • 批准号:
    8674973
  • 财政年份:
    2013
  • 资助金额:
    $ 33.11万
  • 项目类别:

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