LIM2 AND THE LENS CORE SYNCYTIUM

描述（由申请人提供）：纤维细胞之间的细胞间通讯对于透镜体内平衡至关重要，并且已充分确定间隙连接促进相邻纤维细胞之间小分子的扩散。然而，最近我们获得的证据表明，大分子如蛋白质也可以在纤维细胞之间扩散。用于细胞间蛋白质扩散的管道可以是有限的细胞-细胞融合的区域。在透镜核心中细胞之间融合的存在确保了透镜的中心区域作为合胞体发挥功能。核心合胞体的生理意义尚不清楚。Lim 2是透镜中第二丰富的整合膜蛋白。它是claudin超家族的一员，在透镜中具有假定的粘合功能。在初步实验中，通过插入诱变在小鼠中破坏Lim 2基因座，导致Lim 2的功能无效。值得注意的是，在没有Lim 2的情况下，透镜合胞体没有形成。此外，对Lim 2缺失小鼠晶状体的激光分析显示，透镜的内部折射特性受到严重干扰。这些观察结果表明，透镜膜蛋白（Lim 2）的表达，合胞体组织，和屈光功能之间的联系在透镜。目前的应用程序将检查的分子机制，其中大分子扩散之间的透镜细胞，在形成的透镜合胞体中的作用的Lim 2，和合胞体组织和透镜梯度折射率（GRIN）之间的关系。这些研究有望为以前未被怀疑的大分子细胞间扩散和透镜光学质量之间的联系提供新的见解。这些信息将反过来告诉我们眼睛中的图像形成和光学系统中透镜的作用。公共卫生相关性：透镜的作用是将光线聚焦在视网膜上。这个应用程序将检查如何在透镜内的蛋白质的细胞间运动有助于其光学质量。

DESCRIPTION (provided by applicant): Intercellular communication between fiber cells is critical for lens homeostasis and it is well established that gap junctions facilitate the diffusion of small molecules between adjacent fiber cells. Recently, however, we have obtained evidence that large molecules such as proteins can also diffuse between fiber cells. The conduits for intercellular protein diffusion may be regions of limited cell-cell fusion. The presence of fusions between cells in the lens core ensures that the central region of the lens functions as a syncytium. The physiological significance of the core syncytium is not known. Lim2 is the second most abundant integral membrane protein in the lens. It is a member of the claudin super- family and has putative adhesive functions in the lens. In preliminary experiments, the Lim2 locus was disrupted in mice by insertional mutagenesis, resulting in a functional null for Lim2. Significantly, in the absence of Lim2, the lens syncytium did not form. Furthermore, laser analysis of Lim2-null mouse lenses revealed that the internal refractive properties of the lens were profoundly disturbed. These observations suggest a link between the expression of a lens membrane protein (Lim2), syncytial organization, and refractive function in the lens. The current application will examine the molecular mechanism by which macromolecules diffuse between lens cells, the role of Lim2 in the formation of the lens syncytium, and the relationship between syncytial organization and the lens gradient refractive index (GRIN). These studies are expected to provide novel insights into the previously unsuspected link between intercellular diffusion of macromolecules and lens optical quality. This information will, in turn, inform our view of image formation in the eye and the role of the lens in the optical train. PUBLIC HEALTH RELEVANCE: The role of the lens is to focus light sharply on the retina. This application will examine how the intercellular movement of protein within the lens contributes to its optical quality.