Measuring the influence of biomechanical forces on biological processes.

测量生物力学力对生物过程的影响。

• 批准号: RTI-2020-00440
• 负责人: Jones, Nina
• 金额: $ 5.4万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Research Tools and Instruments
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=691740
• 关键词: Measuring; influence; biomechanical; forces; biological

Exposure to biomechanical forces (such as tension, shear stress and pulsatile hemodynamic strain) is essential for normal development of the cardiovascular system, and alterations in force transmission can lead to pathological consequences including kidney and heart disease. The phenomenon by which physical forces are translated into biological responses is called mechanotransduction, and this is regulated via biochemical cues that drive changes in gene and protein expression. To better understand the molecular and cellular signals that are influenced by mechanotransduction, it is necessary to use relatively simple experimental models such as cultures of single cell types. For example, to investigate how an increase in pressure can influence the stiffness of the heart, it is logical to study cardiac fibroblasts as these cells control the level of collagen in the heart. Similarly, to assess how changes in blood pressure and blood filtration influence kidney function, the unique filtering cells of the kidney known as podocytes can be studied. While remarkable strides have been made in growing these unique cell types in static culture, these conditions do not provide the added biomechanical challenge seen in intact organs. The Flexcell FX6000 Tension System requested in this RTI application is a specialized cell stretch apparatus capable of simulating complex in vivo biomechanical forces in simplified in vitro cell culture models. It is the only instrument on the market that allows for controlled multidirectional stretch of cultured cells, mimicking the balloon-like expansion of blood vessels and vascularized tissues. The requested equipment will advance two leading edge research programs at the University of Guelph in eukaryotic cell signalling (Jones) and cardiac physiology (Gillis), and will also be used by a large group of multidisciplinary researchers in cardiovascular science, cancer biology as well as neuroscience on campus. The co-applicants require the Flexcell system to address the following outstanding research questions: 1) How do biomechanical forces influence the adhesive properties of podocytes? 2) How do changes in cell signalling patterns caused by specific genetic mutations lead to podocyte loss? 3) What is the role of biomechanical force is stimulating the migration of neurons and cancer cells? 4) How does a change in blood pressure lead to increased collagen deposition and cardiac fibrosis? 5) What are the cellular pathways involved in reversing cardiac fibrosis in the trout heart? Addressing these questions will provide fundamental insight into the role of biomechanical forces in driving the normal development of complex biological tissues, and how alterations in force transmission lead to tissue dysfunction.

生物力学(如张力、剪应力和脉动血流动力学应变)对于心血管系统的正常发育是必不可少的，力传递的改变可导致包括肾脏和心脏病在内的病理后果。将物理力量转化为生物反应的现象被称为机械转导，这是通过驱动基因和蛋白质表达变化的生化信号来调节的。为了更好地理解受机械转导影响的分子和细胞信号，有必要使用相对简单的实验模型，如单细胞类型的培养。例如，为了研究压力增加如何影响心脏的僵硬程度，研究心脏成纤维细胞是合乎逻辑的，因为这些细胞控制心脏中的胶原水平。同样，为了评估血压和血液滤过的变化如何影响肾脏功能，可以研究肾脏独特的过滤细胞，即足细胞。虽然在静态培养中培养这些独特的细胞类型已经取得了显著的进展，但这些条件并没有提供在完整器官中看到的额外的生物力学挑战。本RTI应用中要求的Flexell FX6000张力系统是一种专门的细胞拉伸设备，能够在简化的体外细胞培养模型中模拟复杂的体内生物机械力。它是市场上唯一一种允许对培养细胞进行受控多方向拉伸的仪器，模拟了血管和血管组织的气球状扩张。所要求的设备将推进圭尔夫大学在真核细胞信号(Jones)和心脏生理学(Gillis)方面的两个尖端研究项目，还将被心血管科学、癌症生物学以及校园神经科学的一大批多学科研究人员使用。共同申请者要求Flexell系统解决以下悬而未决的研究问题：1)生物机械力如何影响足细胞的粘附性？2)特定基因突变导致的细胞信号模式变化如何导致足细胞丢失？3)生物机械力在刺激神经元和癌细胞迁移方面的作用是什么？4)血压的变化如何导致胶原沉积增加和心脏纤维化？5)在鲑鱼心脏逆转心脏纤维化的细胞途径是什么？解决这些问题将从根本上洞察生物力学在推动复杂生物组织正常发展中的作用，以及力传递的变化如何导致组织功能障碍。