Integrating mechanical forces - a cellular mechanodampener

整合机械力 - 细胞机械阻尼器

• 批准号: BB/X007049/1
• 负责人: Angus Wann
• 金额: $ 101.87万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX007049%2F1
• 关键词: Integrating; mechanical; forces; cellular; mechanodampener

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.

为了发展健康的身体组织，细胞通过遵循遗传指导手册来定义其类型和行为。这是对生物学和物理信号的响应进行微调的。相比之下，我们对组织生物学的理解是有限的。这限制了我们对组织形成，成熟和保护终身组织健康的过程的认识。所有组织都需要成功混合生物信号，例如分泌的蛋白质和物理信号。一个例子是血管中的流动，另一个例子是我们移动时骨骼的形成。我们的大部分骨骼都是由软骨形成的，软骨在高度协调的过程中转变为骨骼，称为内侧软骨骨化。我们的关节内衬的软骨必须抵抗这种预编程的过渡，但是形成骨骼的软骨必须控制细胞身份和组织环境中的这种变化。我们骨骼的这种形状既敏感又具有韧性。在青春期小鼠中的研究的最新证据强烈暗示了一个称为原发性纤毛的细胞小室，以保护对细胞类型的程序调整，环境的调节矿化和骨骼的形成。我们假设他们使用它来提高对骨骼成熟的不平等力的反应。现在，我们希望了解哪种软骨细胞亚型使用纤毛来保护其行为，并在武力的背景下以及它们用来启用这一点的消息传递。其次，我们想同时使用小鼠和内部软骨骨化的工程模型来了解纤毛如何帮助这些过程，以及我们如何使用此类模型来了解力学在塑造组织发展和健康中的作用。