Dynamics and regulation of actomyosin contractility in the C. elegans embryo

线虫胚胎肌动球蛋白收缩力的动力学和调节

• 批准号: 8163737
• 负责人: Edwin Marshall Munro
• 金额: $ 29.23万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8163737
• 关键词: Actins; Actomyosin; Address; Affect; Architecture; Behavior; Biochemical; Biological Models; Caenorhabditis elegans; Cell Shape; Cell surface; Cells; Computer Simulation; Computer software; Congenital Abnormality; Crosslinker; Cytokinesis; Data; Development; Disease; Dose; Embryo; F-Actin; Filament; Gene Transfer Techniques; Goals; Health; Heart; Image; Image Analysis; In Vitro; Individual; Java; Kinetics; Life; Link; Malignant Neoplasms; Measurement; Mechanics; Microfilaments; Modeling; Molecular; Molecular Genetics; Motor; Movement; Muscle Contraction; Myosin ATPase; Myosin Type II; Physiological; Physiology; Process; Property; Quantitative Microscopy; RNA Interference; Regulation; Relative (related person); Resistance; Resolution; Shapes; Skeletal Muscle; Surface; System; Testing; Tissues; Work; alpha Actinin; anillin; base; cell motility; cofilin; crosslink; density; experimental analysis; genetic manipulation; inhibitor/antagonist; innovation; insight; light microscopy; profilin 1; research study; response; rho; simulation; tool

DESCRIPTION (provided by applicant): The broad goal of this study is to understand the basic principles that govern actomyosin contractility in non-muscle cells, using C. elegans as a model system. Unlike in skeletal muscle contraction, where force is produced by stable almost crystalline arrays of actin filaments and myosin motors, contractility in non-muscle cells is the global consequence of distributed local force-generating interactions among motors and filaments that rapidly assemble, move and dissemble as they interact. Understanding how organized cell-scale contractile behaviors emerge from these local interactions, and how local regulation of the individual players "tunes" the same system to produce different behaviors, is fundamental to understanding how cells regulate contractility during normal development and physiology and how it is dysregulated in disease. We will address these challenges in the context of a fundamental and widely used mode of contractility - called focal contractility - in which the periodic assembly, contraction and disassembly of contractile networks drive transient deformations of the cell surface that are rectified to produce cell shape change, cortical flow and tissue deformation. The C. elegans embryo provides a uniquely tractable opportunity to study focal contractility at the surface of single large cells using well-developed tools for molecular genetic manipulation, transgenesis, and high-resolution quantitative light microscopy. We will use a tightly integrated combination of quantitative imaging, experimental manipulations, and predictive computer simulations to ask the following questions: 1) How does the focal contractility cycle work? i.e. what governs the initiation and termination of focal contractions? 2) How is focal contractility regulated by tuning local myosin activity, and the local kinetics of myosin and actin filament assembly and disassembly? 3) Can detailed computer simulations, based on what we know about the properties of and interactions among actin filaments, myosin, crosslinkers and their key regulators, reproduce the macroscopic dynamics of focal contractility and its regulation and reveal the fundamental underlying principles? Given the extensive conservation of molecular players involved in actomyosin contractility, our work will have direct relevance to understanding contractility in many other contexts, both in health and disease. PUBLIC HEALTH RELEVANCE: The work proposed here aims to elucidate fundamental principles underlying the organization and regulation of actomyosin contractility in non-muscle cells, using C. elegans as a model system. Actomyosin contractility is fundamental to normal development and physiology and is at the heart of processes that underlie birth defects (eg: neurulation) and that go awry in disease (e.g. cell motility in cancer). Because the basic machinery that governs contractility is highly conserved, the results of this work should have direct implications for the understanding of these aberrant states.

描述（由申请人提供）：本研究的主要目标是使用秀丽隐杆线虫作为模型系统，了解控制非肌肉细胞肌动球蛋白收缩性的基本原理。与骨骼肌收缩不同，在骨骼肌收缩中，力是由肌动蛋白丝和肌球蛋白马达的稳定的几乎晶体阵列产生的，非肌肉细胞的收缩性是马达和肌丝之间分布式局部产生力相互作用的整体结果，它们在相互作用时快速组装、移动和分解。了解有组织的细胞尺度收缩行为如何从这些局部相互作用中产生，以及个体参与者的局部调节如何“调整”同一系统以产生不同的行为，对于理解细胞在正常发育和生理过程中如何调节收缩性以及在疾病中如何失调是至关重要的。我们将在一种基本且广泛使用的收缩模式（称为局灶收缩性）的背景下解决这些挑战，其中收缩网络的周期性组装、收缩和分解驱动细胞表面的瞬时变形，这些变形被纠正以产生细胞形状变化、皮质流动和组织变形。线虫胚胎提供了一个独特的易处理的机会，可以使用成熟的分子遗传操作、转基因和高分辨率定量光学显微镜工具来研究单个大细胞表面的局灶收缩性。我们将使用定量成像、实验操作和预测计算机模拟的紧密结合来提出以下问题：1）局灶收缩性循环如何工作？即什么控制局灶性收缩的开始和终止？ 2）如何通过调节局部肌球蛋白活性以及肌球蛋白和肌动蛋白丝组装和拆卸的局部动力学来调节局部收缩力？ 3）基于我们对肌动蛋白丝、肌球蛋白、交联剂及其关键调节剂的特性和相互作用的了解，详细的计算机模拟能否重现局灶收缩性及其调节的宏观动力学并揭示基本原理？鉴于参与肌动球蛋白收缩性的分子参与者的广泛保护，我们的工作将与了解许多其他情况下的收缩性（无论是健康还是疾病）直接相关。 公共健康相关性：本文提出的工作旨在以秀丽隐杆线虫作为模型系统，阐明非肌肉细胞中肌动球蛋白收缩性的组织和调节的基本原理。肌动球蛋白收缩性是正常发育和生理学的基础，并且是出生缺陷（例如神经形成）和疾病中出错（例如癌症中的细胞运动）过程的核心。由于控制收缩性的基本机制是高度保守的，因此这项工作的结果应该对理解这些异常状态具有直接影响。