DYNAMICS OF THE ACTIN CYTOSKELETON IN OSTEOCLASTS

项目摘要：骨骼力量是通过严格控制骨形成的平衡来实现的 和骨骼退化。负责这种调节降解的细胞是破骨细胞，大的 单核细胞系的多核细胞。破骨细胞经历一个周期的活动，包括 迁移、极化、骨吸收和去极化。这些活动需要整合素的参与 以及肌动蛋白细胞质的广泛重排。破骨细胞不能经历这些过程 导致细胞功能减弱，并可能对骨骼健康造成严重后果，如 骨化症。这项建议的目的是研究破骨细胞中肌动蛋白细胞骨架的动力学。 在迁移和极化等事件中，并了解这一过程所需的细胞元素 正常破骨细胞功能的方面。这项提议的第一个目标是针对分子马达。 肌球蛋白IIA，它与动态肌动蛋白结构密切相关，参与破骨细胞迁移和 极化。这种马达的潜在功能将通过抑制其活动和通过 在贩卖活细胞之后。第二个目标的目标是了解 破骨细胞中的其他肌球蛋白亚型，特别是当它们可能与细胞信号通路有关时。最后， 我们已经确定了破骨细胞中具有特定分布的原肌球蛋白的异构体。原肌球蛋白是 丝状蛋白可以调节肌动蛋白的稳定性，以及它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研究它们的功能。 表达，并确定对破骨细胞肌动蛋白重排的影响。这些研究将提供 对这一动态细胞类型中肌动蛋白细胞骨架介导的关键过程的新理解。 相关性：正在进行的骨骼形成和降解过程必须保持平衡，以保持 骨骼健康。骨骼降解是由称为破骨细胞的细胞执行的，这种细胞依赖于 它们的内部形状和活动结构。这项工作的目标是了解一些 调节破骨细胞形状的蛋白质，作为理解破骨细胞活性的更大努力的一部分 这些细胞是受调控的。

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.