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Primary Cilia as Mechanotransducers in Bone

初级纤毛作为骨骼中的机械传感器

基本信息

批准号：
7413574
负责人：
Christopher Rae Jacobs
金额：
$ 14.75万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-21 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7413574
关键词：
Activities of Daily Living Affect Alleles Biology Bone Tissue Calcium Signaling Cells Cilia Condition Cultured Cells Data Densitometry Dinoprostone Disease Disruption Etiology Exploratory/Developmental Grant Frequencies Future Genes Health Human In Vitro Individual Intercellular Fluid Kidney Knock-out Knockout Mice Lead MAP Kinase Gene Mechanics Metabolism Modeling Molecular Mus Mutant Strains Mice Osteoblasts Osteocytes Osteogenesis Osteoporosis Pathology Phenotype Phosphorylation Physical activity Polycystic Kidney Diseases Range Renal tubule structure Reporter Genes Research Risk Role Series Signal Transduction Skeletal system Small Interfering RNA Staining method Stains Structure Testing Tissues Transducers Transgenes Wild Type Mouse Work base bone bone cell cell type fluid flow in vivo novel release of sequestered calcium ion into cytoplasm research study response sensor ulna

项目摘要

DESCRIPTION (provided by applicant): Physical loading is known to be a potent regulator of bone tissue metabolism. However, the cellular mechanisms that allow bone to sense and respond to load are not understood. Our prior work has suggested that pericellular dynamic fluid flow is an important cellular physical signal for both osteoblasts and osteocytes. Although we have elaborated many aspects of intracellular signaling activated by dynamic fluid flow, we have not uncovered the molecular mechanotransduction mechanism which initiates these signals. In this application, we propos that primary cilia are acting as cellular flow sensors and are thereby contribute to mechanotransduction in bone. We have collected unique preliminary data that suggest that primary cilia may also act as flow sensors in bone. Specifically, our results suggest that osteoblastic cells express primary cilia, that dynamic flow is able to mobilize these cilia, and that disruption of the cilia interferes with the ability of the cells to sense dynamic flow. The central hypothesis of this two year project is that dynamic fluid flow due to loading regulates bone cell metabolism via a molecular mechanism involving the primary cilia. To test this hypothesis we will undertake a series of bone in vitro and in vivo experiments to determine if primary cilia act as flow transducers in bone cells in cell culture experiments in highly controlled accurate flow conditions (aim 1), and disrupting primary cilia in vivo inhibits bone's ability to adapt to external mechanical loading (aim 2). If our hypothesis is found to be true it would represent a breakthrough and shift of paradigm in the search for the mechanism of mechanotransduction in bone. Thus, although the evidence for the primary cilia's function as a flow sensor is still relatively immature, this project has potentially profound implications for future research in terms of mechanoregulation of bone in both health and disease. The etiologies of several diseases are related to pathology in the ability of bone to adapt its structure to mechanical demand, including osteoporosis that affects over 25 million people. In this project, we focus on a novel cellular sensor, the primary cilia, which may be responsible for mechanotransduction in bone. If our hypothesis is found to be true it would represent a breakthrough and shift of paradigm in bone biology and, thus, although the evidence for the primary cilia's function as a mechanical sensor is still relatively immature, this project has potentially profound implications for future research in terms of mechanoregulation of bone in both health and disease.

描述（由申请人提供）：已知物理负荷是骨组织代谢的有效调节剂。然而，骨骼感知和响应负荷的细胞机制尚不清楚。我们之前的工作表明，细胞周动态流体流动对于成骨细胞和骨细胞来说都是重要的细胞物理信号。尽管我们已经详细阐述了动态流体流动激活的细胞内信号传导的许多方面，但我们尚未揭示启动这些信号的分子力转导机制。在此应用中，我们提出初级纤毛充当细胞流传感器，从而有助于骨中的机械转导。我们收集了独特的初步数据，表明初级纤毛也可能充当骨骼中的流量传感器。具体来说，我们的结果表明，成骨细胞表达初级纤毛，动态流能够动员这些纤毛，并且纤毛的破坏会干扰细胞感知动态流的能力。这个为期两年的项目的中心假设是，由于负载而产生的动态流体流动通过涉及初级纤毛的分子机制调节骨细胞代谢。为了检验这一假设，我们将进行一系列的体外和体内骨骼实验，以确定在高度控制的精确流动条件下的细胞培养实验中，初级纤毛是否充当骨细胞中的流动传感器（目标 1），并且破坏体内初级纤毛会抑制骨骼适应外部机械负载的能力（目标 2）。如果我们的假设被证明是正确的，这将代表着在寻找骨骼中的力转导机制方面的突破和范式的转变。因此，尽管初级纤毛作为流量传感器的功能的证据仍然相对不成熟，但该项目对健康和疾病中骨骼机械调节的未来研究具有潜在的深远影响。多种疾病的病因与骨骼调整其结构以适应机械需求的能力有关，其中包括影响超过 2500 万人的骨质疏松症。在这个项目中，我们重点研究一种新型细胞传感器，即初级纤毛，它可能负责骨骼中的机械传导。如果我们的假设被证明是正确的，它将代表骨生物学的突破和范式转变，因此，尽管初级纤毛作为机械传感器的功能的证据仍然相对不成熟，但该项目对健康和疾病中骨骼机械调节的未来研究具有潜在的深远影响。