Primary Cilia as Mechanotransducers in Bone

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，允许骨感知和响应负荷的细胞机制尚不清楚。我们先前的工作表明，细胞周围的动态流体流动是一个重要的细胞物理信号，为成骨细胞和骨细胞。虽然我们已经阐述了许多方面的细胞内信号激活的动态流体流动，我们还没有发现的分子mechanotransduction机制，启动这些信号。在这个应用中，我们提出，初级纤毛作为细胞流量传感器，从而有助于骨中的机械转导。我们已经收集了独特的初步数据，表明初级纤毛也可以作为骨中的流量传感器。具体来说，我们的研究结果表明，成骨细胞表达初级纤毛，动态流动能够动员这些纤毛，纤毛的破坏干扰细胞的能力，以感受到动态流动。这个为期两年的项目的中心假设是，由于负载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。为了验证这一假设，我们将进行一系列骨体外和体内实验，以确定在高度控制的精确流动条件下，在细胞培养实验中，初级纤毛是否充当骨细胞中的流动传感器（目的1），以及在体内破坏初级纤毛是否抑制骨适应外部机械负荷的能力（目的2）。如果我们的假设被证实，这将代表着在骨中机械力传导机制的研究中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，但该项目对未来在健康和疾病中骨的机械调节方面的研究具有潜在的深远影响。几种疾病的病因与骨骼使其结构适应机械需求的能力的病理学有关，包括影响超过2500万人的骨质疏松症。在这个项目中，我们专注于一种新的细胞传感器，初级纤毛，这可能是负责在骨的机械转导。如果我们的假设被发现是真的，这将代表骨生物学的突破和范式的转变，因此，虽然初级纤毛作为机械传感器的功能的证据仍然相对不成熟，但该项目对未来的研究在健康和疾病中的骨机械调节方面具有潜在的深远影响。

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.