Molecular mechanisms for length adaptation in smooth muscle cells

平滑肌细胞长度适应的分子机制

• 批准号: RGPIN-2017-04976
• 负责人: Seow, Chun
• 金额: $ 3.5万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=630487
• 关键词: Molecular; mechanisms; length; adaptation; smooth

Smooth muscle is found in hollow organs such as the stomach, intestine, urinary bladder, blood vessels, and airways. Contraction of the muscle allows the organs to perform functions like urination, moving the contents along the digestive tract, and the control of blood pressure and airway resistance. Because most of the hollow organs undergo large changes in volume while performing their functions, smooth muscle is required to maintain its ability to contract over a working length-range much larger than that in skeletal muscle. For a long time the theory explaining skeletal muscle contraction was also used to explain smooth muscle contraction, despite the fact that it cannot accommodate the large working length-range of smooth muscle. Increasingly it has been recognized that the subcellular structure of smooth muscle, call the cytoskeleton, is much more “fluid” than that in skeletal muscle; it is able to drastically alter its shape while maintaining its ability to contract. This is believed to be due to a transformation process called length adaptation during which plastic restructuring of the cytoskeleton takes place. It is also believed that the transformation allows the contractile filaments, called myosin and actin filaments, to maintain contact with each other and generate tension. The process is initiated when a large change in the muscle length occurs, and it involves sequential events with initial disassembly of existing cytoskeletal structures followed by reassembly of the structure to fit the new cell length. However, the molecular mechanism underlying this adaptation process is largely unknown. The goal of this research program is to unravel the molecular mechanism of length adaptation, a unique smooth muscle behavior essential for proper function of the cell. Our laboratory is a leader in this area of research (we coined the term “length adaptation” which has now appeared in physiology textbooks). There is evidence suggesting that the myosin and actin filaments depolymerize and repolymerize during length adaptation. We plan to investigate the temporal and spatial events associated with polymerization of myosin and actin filaments and how they are linked by adaptor (or connector) proteins to form different shapes of cytoskeleton tailored to different cell dimensions. Knowledge gained from the research will fill a void in our understanding of the molecular mechanisms of length adaptation in smooth muscle and other cell types that utilize deformation of the cytoskeleton and recruitment and redistribution of myosin molecules in cell functions like tension generation, movement, and cell division.

平滑肌存在于胃、肠、膀胱、血管和气道等中空器官中。肌肉的收缩使器官能够执行诸如排尿、使内容物沿着消化道移动以及控制血压和气道阻力等功能。由于大多数中空器官在执行其功能时体积会发生很大变化，因此需要平滑肌在比骨骼肌大得多的工作长度范围内保持其收缩能力。长期以来，解释骨骼肌收缩的理论也被用来解释平滑肌收缩，尽管它不能适应平滑肌的大工作长度范围。越来越多的人认识到，平滑肌的亚细胞结构，称为细胞骨架，比骨骼肌更“流动”;它能够在保持收缩能力的同时急剧改变其形状。这被认为是由于一个称为长度适应的转化过程，在此过程中细胞骨架发生塑性重组。人们还认为，这种转化允许收缩性细丝（称为肌球蛋白和肌动蛋白细丝）保持相互接触并产生张力。当肌肉长度发生大的变化时，该过程开始，并且它涉及顺序事件，其中现有细胞骨架结构的初始拆卸，然后是结构的重新组装以适应新的细胞长度。然而，这种适应过程的分子机制在很大程度上是未知的。这项研究计划的目标是解开长度适应的分子机制，这是一种独特的平滑肌行为，对细胞的正常功能至关重要。我们的实验室是这一研究领域的领导者（我们创造了“长度适应”这个术语，现在已经出现在生理学教科书中）。有证据表明，肌球蛋白和肌动蛋白丝在长度适应过程中发生变性和再变性。我们计划研究与肌球蛋白和肌动蛋白丝聚合相关的时间和空间事件，以及它们如何通过适配器（或连接器）蛋白连接，以形成适合不同细胞尺寸的不同形状的细胞骨架。从研究中获得的知识将填补我们对平滑肌和其他细胞类型中长度适应的分子机制的理解中的空白，这些细胞类型利用细胞骨架的变形以及肌球蛋白分子在细胞功能中的募集和重新分布，如张力产生，运动和细胞分裂。