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:10470176
- 负责人:
- 金额:$ 32.78万
- 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
- 来源:
- 关键词:ActinsAdultAge-Related Bone LossAnimal ModelBone TissueCRISPR/Cas technologyCalcium SignalingCell LineCellsClinicalDevelopmentEconomic BurdenElderlyEngineeringExerciseGene ExpressionGoalsHealthHealth Care CostsHindlimb SuspensionIn VitroIncidenceKnock-outKnockout MiceKnowledgeMalignant neoplasm of lungMalignant neoplasm of prostateMissionModelingMusMuscleNucleotidesOsteocytesOsteogenesisOsteoporosisOsteoporosis preventionOutcomeP2Y2 receptorParalysedPersonal SatisfactionPhosphorylationPhysical ExercisePhysical activityPlayPrevalencePrevention strategyPublic HealthPurinoceptorRoleSeriesSignal TransductionStress FibersTestingTherapeuticTherapeutic AgentsTissuesUnited States National Institutes of Healthagedaging populationantagonistbasebonebone lossbone masscofilinconditional knockoutdentin matrix protein 1efficacy evaluationexperimental studyfluid flowfracture riskimprovedin vivoinhibitorinnovationmalignant breast neoplasmmechanical loadmechanical propertiesmechanotransductionnew therapeutic targetnovel therapeutic interventionnovel therapeuticsosteoporosis with pathological fractureoverexpressionpreventprotein expressionresponsetherapy designtreadmill
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,发病率越来越高,并有很高的相关经济负担。
这一重大的临床问题因缺乏增加骨骼的治疗策略而进一步复杂化。
形成并提高组织强度。骨形成是骨细胞对机械反应的一种功能
体力活动和锻炼时的负荷量。骨细胞的嘌呤能信号转导途径
核苷酸在调节骨骼对负荷的适应性方面起着关键作用。尤其是我们发现
P2Y2受体下调骨细胞对负荷的敏感性,机械敏感性的丧失是
伴随着通过cofilin磷酸化的肌动应激纤维形成(ASFF)的增加。这些
研究结果意义重大,因为他们建议将P2Y2信号作为增强
骨细胞机械转导和增加骨形成。然而,P2Y2影响的程度
通过ASFF调节骨细胞对负荷的敏感性来形成骨仍然是未知的。这些差距存在于
知识限制了我们增加骨形成和减少骨形成的新治疗策略的开发
老龄化人口中的骨折风险。我们的长期目标是预防骨质疏松症,降低骨折风险
人口老龄化。本研究的目的是确定通过P2Y2的嘌呤能信号转导的作用
受体在调节负荷时的合成代谢反应。这项研究的前提是阻断P2Y2
信号转导具有预防年龄相关性骨丢失和降低骨折风险的治疗潜力。中环
假说认为,阻断P2Y2信号将增加骨细胞对负荷的敏感性,从而允许更大的
骨量和组织强度对负荷的响应增加。核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信号在体外对骨细胞的影响程度
通过cofilin磷酸化调节asff的敏感性和对负荷的总体反应。我们的方法是
AIM 1利用CRISPR/Cas9建立的骨细胞敲除细胞系在体外检测它们对
流体流动。目标2将确定体内P2Y2表达对骨形成的贡献程度
对装卸的响应。我们在目标2中的方法将规定跑步机锻炼和后肢
对以骨细胞P2Y2表达为靶点的条件性基因敲除小鼠的固定。目标3将研究
选择性P2Y2R抑制剂AR-C118925增强老年人负荷后合成代谢反应的效果
此外,它还能防止与年龄相关的骨质流失。我们在目标3中的方法将处理野生型和P2Y2-
用AR-C118925基因敲除小鼠,以识别非骨细胞特有的非靶标效应。这项研究是
创新是因为它1)评估了一种用于促进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来建立作为增加骨骼的独特机制的P2Y2信号
质量。总体而言,这项研究具有重要意义,因为我们希望它能证明
以P2Y2R信号为靶点,增加骨形成,降低骨折风险。
项目成果
期刊论文数量(0)
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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:
$ 32.78万 - 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:
10680508 - 财政年份:2020
- 资助金额:
$ 32.78万 - 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:
$ 32.78万 - 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:
$ 32.78万 - 项目类别:
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