Control of Actin Assembly and Cell Migration by Actin-Regulating Proteins

肌动蛋白调节蛋白对肌动蛋白组装和细胞迁移的控制

• 批准号: 7664923
• 负责人: ANDERS E CARLSSON
• 金额: $ 26.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7664923
• 关键词: Actin-Binding Protein; Actins; Algorithms; Area; Bacterial Infections; Behavior; Binding; Biochemical; British Columbia; Cell Shape; Cell Surface Receptors; Cell model; Cells; Chemicals; Cities; Clinical; Code; Collaborations; Complex; Computers; Cytochalasins; Cytoskeleton; Data; Filament; Generations; Growth; Guanosine Triphosphate Phosphohydrolases; Hydrolysis; Individual; Laboratories; Laws; Length; Letters; Link; Malignant Neoplasms; Measurement; Measures; Mechanics; Methodology; Methods; Microfilaments; Modeling; Modification; Motion; Myosin ATPase; Neighborhoods; Network-based; Phosphatidylinositols; Physics; Process; Proteins; Publishing; Regulation; Regulatory Pathway; Research; Schools; Science; Scientist; Series; Signal Pathway; Signal Transduction; Signaling Protein; Stimulus; Stress; Students; Testing; Time; Universities; Washington; Wasps; Width; Work; base; blebbistatin; cell motility; crosslink; density; depolymerization; flexibility; improved; in vitro testing; inhibitor/antagonist; lectures; mathematical model; migration; molecular scale; monomer; polymerization; professor; programs; research study; response; rho; rho GTP-Binding Proteins; science education; simulation; statistics; three dimensional structure; two-dimensional

DESCRIPTION (provided by applicant): The response of the actin cytoskeleton in cells to external and internal stimuli is a crucial component of cell migration decisions. Assembly of the cytoskeleton is crucial for force generation and directed motion, while disassembly is crucial for maintaining a high density of free monomers to be used in focused polymerization. Migration is controlled by a complex signaling network which begins with cell-surface receptors at the upstream end, and involves actin-binding proteins that interact directly with actin at the downstream end. The actin-binding proteins control key elementary processes such as filament branching, severing, and depolymerization. Central to the cellular signaling network are the Rho GTPases, small signaling proteins which have GTPase activity. The proposed work develops quantitative simulation methods for predicting the response of the actin cytoskeleton to changes in activity of actin binding proteins. These methods will be combined with mathematical modeling of signaling modules involving the Rho GTPAses to predict cell migration behavior as a function of changes in signaling pathways and chemical treatments. The theoretical predictions will be tested by in vitro experiments. Because aberrant behavior of the actin cytoskeleton is a feature of both cancer and many bacterial diseases, the type of understanding that is gained from these studies can have broad clinical impact. The results of the research will be disseminated to a broad audience by two vehicles: Saturday morning public lectures in the Washington University department of physics, and the University City Science Advisory Council (UCSAC). The Saturday morning lecture series has been in place for approximately a decade, and interdisciplinary topics such as biophysical modeling of cell motion are warmly welcomed. The audience for these lectures typically numbers a hundred or more, representing a broad cross-section of neighborhoods around the University. Professor Carlsson has given several lectures in this series during the past five years, and intends to continue at approximately this pace. UCSAC, an organization of roughly twenty St. Louis area scientists and other concerned individuals, works to enhance the quality of science education in the University City public schools. Professor Carlsson, currently president of this organization, will work to provide a dedicated summer student program and to expand its science club support.

描述（由申请人提供）：细胞中肌动蛋白细胞骨架对外部和内部刺激的反应是细胞迁移决策的关键组成部分。细胞骨架的组装对于力产生和定向运动至关重要，而拆卸对于维持高密度的游离单体至关重要，用于聚焦聚合。迁移由复杂的信号网络控制，该信号网络从上游端的细胞表面受体开始，涉及肌动蛋白结合蛋白，这些蛋白质在下游端与肌动蛋白直接相互作用。肌动蛋白结合蛋白控制关键基本过程，例如细丝分支，切断和解聚化。细胞信号网络的中心是Rho GTPases，具有GTPase活性的小信号蛋白。提出的工作开发了定量模拟方法，以预测肌动蛋白细胞骨架对肌动蛋白结合蛋白活性变化的反应。这些方法将与涉及Rho GTPases的信号传导模块的数学建模相结合，以预测细胞迁移行为是信号通路和化学处理的变化的函数。理论预测将通过体外实验测试。由于肌动蛋白细胞骨架的异常行为是癌症和许多细菌疾病的特征，因此从这些研究中获得的理解类型可能会产生广泛的临床影响。 这项研究的结果将通过两辆车将其传播给广泛的受众：华盛顿大学物理学系和大学城市科学咨询委员会（UCSAC）的周六早晨的公开演讲。周六早上的讲座系列已经成立了大约十年，并热烈欢迎跨学科的主题，例如细胞运动的生物物理模型。这些讲座的观众通常数量或更多一百个以上，代表了大学周围地区广阔的社区。在过去五年中，卡尔森教授在本系列中进行了几次讲座，并打算以大约这一速度继续。 UCSAC是一个由大约二十名圣路易斯地区科学家和其他有关个人组成的组织，致力于提高大学城公立学校的科学教育质量。目前担任该组织的总裁Carlsson教授将努力提供专门的夏季学生计划并扩大其科学俱乐部的支持。