DYNAMICS OF THE ACTIN CYTOSKELETON IN OSTEOCLASTS

破骨细胞中肌动蛋白细胞骨架的动力学

• 批准号: 7393216
• 负责人: BETH S. LEE
• 金额: $ 25.04万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393216
• 关键词: Actin-Binding Protein; Actins; Activity Cycles; Adhesions; Albers-Schonberg disease; Bone Resorption; Cell physiology; Cells; Cellular Morphology; Class; Co-Immunoprecipitations; Cytoskeletal Proteins; Cytoskeleton; DNA Sequence Rearrangement; Disruption; Elements; Equilibrium; Event; Failure; Generations; Goals; Health; Indium; Integrins; Life; Light; Mediating; Membrane Microdomains; Molecular Motors; Motor; Movement; Myosin ATPase; Nonmuscle Myosin Type IIA; Osteoclasts; Osteogenesis; Physiology; Process; Property; Protein Binding; Protein Isoforms; Protein Overexpression; Proteins; Regulation; Role; Shapes; Signal Pathway; Signal Transduction; Skeletal system; Small Interfering RNA; Staging; Structure; Technology; Testing; Tropomyosin; Work; bone; cell motility; cell type; genetic regulatory protein; knock-down; migration; trafficking

Project Summary: Skeletal strength is achieved through a stringently controlled balance of bone formation and bone degradation. The cells responsible for this regulated degradation are osteoclasts, large multinucleated cells of the monocytic lineage. Osteoclasts undergo a cycle of activity that includes migration, polarization, bone resorption, and depolarization. These events require engagement of integrins and extensive rearrangements of the actin cytoskelton. Failure of osteoclasts to undergo these processes results in diminished cell function and potentially severe consequences to skeletal health such as osteopetrosis. The goal of this proposal is to examine the dynamics of the actin cytoskeleton in osteoclasts during events such as migration and polarization, and to understand the cellular elements required for this aspect of normal osteoclast function. The first aim of this proposal is directed toward the molecular motor myosin IIA, which is closely associatedwith dynamic actin structures involved in osteoclast migration and polarization. The potential functions of this motor will be assessed both by suppressing its activity and by following its trafficking in living cells. The goal of the second aim is directed toward understanding roles of other myosin isoforms in osteoclasts, particularly as they might pertain to cell signaling pathways. Finally, we have identified isoforms of tropomyosins with defined distributions in osteoclasts. Tropomyosins are filamentous proteins that can regulate the stability of actin, as well as its accessibility to other actin-binding proteins. We will examine the functions of these tropomyosins by alternately suppressing or enhancing their expression, and determining the effects on actin rearrangements in osteoclasts. These studies will provide new understanding of crucial processes mediated by the actin cytoskeleton in this dynamic cell type. Relevance: The ongoing process of bone formation and degradation must be kept in balance to maintain skeletal health. Bone degradation is performed by cells called osteoclasts, which depend on changes in their internal shape and structure for activity. The objective of this work is to understand some of the proteins that regulate the shape of osteoclasts, as part of a greater effort to comprehend how the activity of these cells is regulated.

项目摘要：骨骼强度是通过严格控制骨形成的平衡来实现的 和骨质退化。负责这种调节降解的细胞是破骨细胞，大 单核细胞谱系的多核细胞。破骨细胞经历一个活动周期，包括 迁移、极化、骨吸收和去极化。这些事件需要整合素的参与 以及肌动蛋白细胞骨架的广泛重排。破骨细胞未能经历这些过程 导致细胞功能减弱并对骨骼健康产生潜在的严重后果，例如 骨石症。该提案的目标是检查破骨细胞中肌动蛋白细胞骨架的动态 在迁移和极化等事件期间，并了解此过程所需的细胞元素 正常破骨细胞功能的一个方面。该提案的第一个目标是分子马达 肌球蛋白 IIA，与参与破骨细胞迁移的动态肌动蛋白结构密切相关 极化。该电机的潜在功能将通过抑制其活动和通过 在其贩运活细胞之后。第二个目标的目标是理解 破骨细胞中的其他肌球蛋白亚型，特别是它们可能与细胞信号传导途径有关。最后， 我们已经鉴定出在破骨细胞中具有明确分布的原肌球蛋白亚型。原肌球蛋白是 丝状蛋白可以调节肌动蛋白的稳定性及其与其他肌动蛋白结合的可及性 蛋白质。我们将通过交替抑制或增强这些原肌球蛋白的功能来检查它们的功能 表达，并确定对破骨细胞中肌动蛋白重排的影响。这些研究将提供 对这种动态细胞类型中肌动蛋白细胞骨架介导的关键过程的新认识。 相关性：骨骼形成和退化的持续过程必须保持平衡以维持 骨骼健康。骨质降解是由破骨细胞进行的，这取决于破骨细胞的变化 它们的内部形状和活动结构。这项工作的目的是了解一些 调节破骨细胞形状的蛋白质，作为理解破骨细胞活性如何发挥作用的更大努力的一部分 这些细胞受到调节。