Integrating mechanical forces - a cellular mechanodampener

为了发育健康的身体组织，细胞通过遵循遗传指令手册来定义它们的类型和行为。这是通过对生物和物理信号的反应进行微调的。相比之下，我们对组织生物学是如何通过变化的物理力量形成的理解是有限的。这限制了我们对组织形成、成熟和保护组织终身健康的过程的理解。所有组织都需要成功地混合生物信号，如分泌的蛋白质和物理信号。一个例子是血管的流动，另一个例子是我们运动时骨骼的形成。我们的大部分骨骼都是由软骨形成的，软骨在一个高度协调的过程中转变为骨骼，这个过程被称为软骨内成骨。我们关节的软骨必须抵抗这种预先编程的转变，但形成骨骼的软骨必须控制细胞身份和组织环境的这种变化。我们骨骼的这种形状对物理力量既敏感又有弹性。最近对青春期小鼠的研究表明，一种被称为初级纤毛的微小细胞区室在保护细胞类型的程序化调整、调节环境的矿化和软骨形成骨骼方面发挥着重要作用。我们假设，随着我们骨骼的成熟，它们用它来平衡对不平等力量的反应。我们现在希望了解哪些软骨细胞亚型使用纤毛来保护它们在力的背景下的行为，以及它们使用什么信息来实现这一点。其次，我们想使用小鼠和软骨内成骨的工程模型来了解纤毛如何帮助这些过程，以及我们如何使用这些模型来理解力学在塑造组织发育和健康中的作用。

To develop healthy body tissues, cells define their type and behaviour by following a genetic instruction manual. This is fine-tuned by responses to both biological and physical signals. Comparatively, our understanding of how tissue biology is shaped by changing physical forces is limited. This limits our appreciation of both tissue formation, maturation and of the processes that safeguard life-long tissue health. All tissues require the successful mixing of biological signals such as secreted proteins and physical signals. One example is flow in blood vessels, another is the formation of our skeleton whilst we move. Much of our skeleton is formed from cartilage, which transitions to bone in a highly coordinated process called endochondral ossification. The cartilage lining our joints must resist this pre-programmed transition but the cartilage that forms bone must control this change in cell identity and tissue environment. This shaping of our skeleton is both sensitive and resilient to physical forces. Recent evidence from studies in adolescent mice, strongly implicates a tiny compartment of cell called primary cilia in protecting programmed adjustments to cell type, regulated mineralisation of the environment and the formation of bone from cartilage. We hypothesise they use it to level out responses to unequal forces as our skeleton matures. We now wish to understand which cartilage cell subtypes use cilia to protect their behaviour in the context of force and what messaging they use to enable this. Secondly, we would like to use both mice and an engineered model of endochondral ossification to understand how cilia aid these processes and how we can use such models to understand the role of mechanics in shaping tissue development and health.