Fluid Shear Stress and Osteoblast Apoptosis
流体剪切应力和成骨细胞凋亡
基本信息
- 批准号:6878039
- 负责人:
- 金额:$ 31.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-04-01 至 2008-03-31
- 项目状态:已结题
- 来源:
- 关键词:3T3 cellsJUN kinaseSDS polyacrylamide gel electrophoresisapoptosisbiological fluid transportbiological signal transductionbiomechanicsbody fluid osmolaritybone developmentcolorimetrycysteine endopeptidasesenzyme induction /repressionenzyme inhibitorsflow cytometryimmunoprecipitationlaboratory ratmitogen activated protein kinaseosteoblastsphosphatidylinositol 3 kinasephosphorylationprostaglandinsshear stresstensile strengthterminal nick end labelingtissue /cell culturewestern blottings
项目摘要
DESCRIPTION (provided by applicant): It is well known that mechanical loading increases formation and remodeling of bone. Bone mass is increased in response to exercise, while chronic unloading of bone, such as occurs during prolonged bed rest and in microgravity during space flight, results in atrophy of bone. The broad aim of our research is to understand the cellular and molecular mechanisms that regulate mechanically-induced bone formation. Experimental studies suggest that mechanically-induced bone formation may be stimulated by fluid shear stress (FSS)-induced activation of osteoblasts. Mechanical activation of osteoblasts is thought to result from the movement of interstitial fluid through the porous spaces inside bone that subjects osteoblasts to FSS during high impact loading. However, the cellular mechanisms through which FSS promotes an anabolic response in osteoblasts are not clearly understood. Interestingly, a large proportion of osteoblasts at sites of bone remodeling are destined to undergo programmed cell death (apoptosis). Therefore, processes that inhibit osteoblast apoptosis may be effective in increasing bone formation and improving bone strength in normal and disease states. Our preliminary studies indicate that mechanical stimulation of osteoblasts in vitro, by exposure to steady fluid shear stress, inhibits osteoblast apoptosis. Therefore, in this application we propose experiments that are designed to investigate the signaling mechanisms through which FSS promotes the survival of osteoblasts. We will: (1) determine the mechanisms through which FSS regulates intracellular signaling pathways involved in control of apoptosis, and (2) determine the role of temporal shear gradients in the anti-apoptotic response of osteoblasts to FSS. The long-term goal of this research is to identify strategies for improving bone health by better understanding the cellular and molecular mechanisms that regulate osteoblast survival. In this application, we propose to use an in vitro cell culture model to test the hypothesis that exposure of cells to either steady or pulsatile fluid shear stress regulates osteoblast survival through specific cellular processes, including activation of the PI3-kinase/Akt and MAPK signaling pathways and inhibition of caspase activation. We will use primary cultures of rat calvarial osteoblasts, and osteoblast cell lines, including MC3T3-E1 and UMR106.01 cells, to investigate the cellular mechanisms that regulate apoptosis.
描述(由申请人提供):众所周知,机械负荷会增加骨骼的形成和重塑。骨骼对运动的响应增加,而骨骼的慢性卸载,例如在长时间的床休息期间和在太空飞行过程中的微重力中发生,会导致骨骼萎缩。我们研究的广泛目的是了解调节机械诱导骨形成的细胞和分子机制。实验研究表明,机械诱导的骨形成可能会受到液体剪切应力(FSS)诱导的成骨细胞激活的刺激。据认为,成骨细胞的机械激活是由于间质流体通过骨骼内部的多孔空间的运动而导致的,在高冲击载荷期间,将成骨细胞带到FSS。但是,FSS促进成骨细胞中合成代谢反应的细胞机制尚不清楚。有趣的是,骨重塑部位的大部分成骨细胞注定要经历程序性细胞死亡(凋亡)。因此,抑制成骨细胞凋亡的过程可能有效地增加骨形成并改善正常状态和疾病状态的骨骼强度。我们的初步研究表明,通过暴露于稳定的液体剪切应力来抑制成骨细胞细胞凋亡,从而在体外刺激成骨细胞。因此,在此应用中,我们提出了旨在研究FSS促进成骨细胞存活的信号传导机制的实验。我们将:(1)确定FSS调节涉及控制凋亡的细胞内信号传导途径的机制,(2)确定时间剪切梯度在成骨细胞对FSS的抗凋亡反应中的作用。这项研究的长期目标是通过更好地了解调节成骨细胞存活的细胞和分子机制来确定改善骨骼健康的策略。在此应用中,我们建议使用体外细胞培养模型来测试细胞暴露于稳定或搏动流体剪切应力的假设,可以通过特定的细胞过程调节成骨细胞的生存,包括激活PI3-激酶/AKT和MAPK信号传导途径和Caspase激活的抑制。我们将使用大鼠颅骨成骨细胞的原发性培养物以及包括MC3T3-E1和UMR106.01细胞在内的成骨细胞系,以研究调节细胞凋亡的细胞机制。
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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Fredrick M Pavalko其他文献
Fredrick M Pavalko的其他文献
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{{ truncateString('Fredrick M Pavalko', 18)}}的其他基金
Role of Src Kinase in Mechanically-Induced Bone Formation
Src 激酶在机械诱导骨形成中的作用
- 批准号:
9174915 - 财政年份:2017
- 资助金额:
$ 31.83万 - 项目类别:
Mechanical Signaling through Osteoblast Focal Adhesions
通过成骨细胞局部粘连的机械信号传导
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8076711 - 财政年份:2007
- 资助金额:
$ 31.83万 - 项目类别:
Mechanical Signaling through Osteoblast Focal Adhesions
通过成骨细胞局部粘连的机械信号传导
- 批准号:
7622088 - 财政年份:2007
- 资助金额:
$ 31.83万 - 项目类别:
Mechanical Signaling through Osteoblast Focal Adhesions
通过成骨细胞局部粘连的机械信号传导
- 批准号:
7194424 - 财政年份:2007
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$ 31.83万 - 项目类别:
Mechanical Signaling through Osteoblast Focal Adhesions
通过成骨细胞局部粘连的机械信号传导
- 批准号:
7431790 - 财政年份:2007
- 资助金额:
$ 31.83万 - 项目类别:
Mechanical Signaling through Osteoblast Focal Adhesions
通过成骨细胞局部粘连的机械信号传导
- 批准号:
7847550 - 财政年份:2007
- 资助金额:
$ 31.83万 - 项目类别:
Mechanical Signaling through Osteoblast Focal Adhesions
通过成骨细胞局部粘连的机械信号传导
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