EXPRESSION AND REGULATION OF GAP JUNCTIONS IN BONE CELLS

拟议的研究试图确定分子机制， 骨中间隙连接蛋白的表达和功能受到控制 细胞 参与骨形成和重塑的细胞必须能够 共同发挥作用，有效地维持骨骼， 对局部和激素刺激的反应。 其中一个主要的方式， 细胞之间的交流是通过缝隙连接。 间隙 连接是由膜蛋白的六聚体组成， 连接蛋白在相邻的细胞质之间形成水通道， 细胞 这些结构允许细胞的电和化学耦合 并且在许多肿瘤的细胞生长、肿瘤发生和发育中是重要的。 不同的细胞 缝隙连接以前已经在骨中被发现 电子显微镜下的细胞。 对这一建议的初步研究已经 显示人类和大鼠成骨细胞和细胞系表达三种 间隙连接蛋白的连接蛋白家族的不同成员。 此外，成骨细胞的沟通能力不同， 通过缝隙连接，不同的连接蛋白 在成骨细胞的细胞间通讯中扮演不同的角色。 因为很多 的连接蛋白已被克隆和测序，现在有可能 在正常情况下不表达的细胞中表达单个间隙连接蛋白 来研究它们的功能。 概述的研究 该提案将定义不同的缝隙连接蛋白如何 有助于成骨细胞中的细胞间通讯，以及 这些蛋白质的表达和功能受局部和 系统介质如细胞因子、激素和信号传导介质 影响骨细胞功能的信号转导。 这些研究可以 阐明调节骨细胞功能的重要机制， 并提出了影响骨重建的新方法。

The proposed studies seek to define the molecular mechanisms by which the expression and function of gap junction proteins is controlled in bone cells. The cells involved in bone formation and remodeling must be able to function in concert to effectively maintain bone, and they do so in response to local and hormonal stimuli. One of the major ways in which cells communicate with each other is through gap junctions. Gap junctions are composed of hexamers of integral membrane proteins called connexins which form aqueous channels between the cytoplasm of adjacent cells. These structures allow electrical and chemical coupling of cells and are important in cell growth, oncogenesis, and development in many different cells. Gap junctions have been identified previously in bone cells by electron microscopy. Preliminary studies for this proposal have shown that human and rat osteoblastic cells and cell lines express three different members of the connexin family of gap junction proteins. Furthermore, osteoblastic cells differed in their ability to communicate through gap junctions, and the different connexins appear to play different roles in cell-cell communication in osteoblasts. Because many of the connexins have been cloned and sequenced, it is now possible to express individual gap junction proteins in cells that do not normally express them in order to study their function. The studies outlined in this proposal will define how the different gap junction proteins contribute to cell-cell communication in osteoblastic cells, and how the expression and function of these proteins are controlled by local and systemic mediators such as cytokines, hormones, and mediators of signal transduction that affect bone cell function. These studies may thereby elucidate important mechanisms by which bone cell function is regulated, and suggest novel ways in which bone remodeling can be influenced.