Regulation of Lens Cell Coupling and Differentiation

据估计，白内障影响了2050万美国人的视力。在以前的研究中，我们开发了一种无血清的原代鸡胚透镜细胞培养系统（DCDMLs），并使用它来显示成纤维细胞生长因子（FGF），在体内透镜赤道的水平，上调间隙连接介导的细胞间通讯和上皮细胞向纤维分化的标志物的表达。最近，我们已经证明FGF促进这些过程的能力完全依赖于晶状体衍生的骨形态发生蛋白（BMP）-4和/或7。在透镜中过度表达BMP抑制剂的转基因小鼠中的研究支持了正常透镜发育和功能需要FGF和BMP信号通路的假设。另一种眼生长因子TGF β 3参与前囊下白内障（ASC）的发展。这里显示的初步结果表明，TGF β 3是第一个以依赖于FGF浓度的方式干扰透镜细胞间隙连接的生理相关生长因子。本研究的目的是：（1）确定TGF β 3干扰透镜细胞间缝隙连接介导的细胞间通讯的信号转导机制，（2）阐明BMP 4在转基因小鼠次级纤维分化中的体内作用。 本摘要经过修改，以符合该奖项的两年长度。

Cataracts affect the vision of an estimated 20.5 million Americans. In previous investigations, we developed a serum-free primary embryonic chick lens cell culture system (DCDMLs) and used it to show that fibroblast growth factor (FGF), at levels available to the lens equator in vivo, upregulates both gap junction-mediated intercellular communication and expression of markers of epithelial-tofiber differentiation. More recently, we have demonstrated that the ability of FGF to promote these processes is completely dependent on lens-derived bone morphogenic protein (BMP) -4 and/or 7. Studies in transgenic mice overexpressing a BMP inhibitor in the lens support the hypothesis that normal lens development and function reguires both the FGF and BMP signaling pathways. Another ocular growth factor, TGFj3, is involved in the development of anterior subcapsular cataracts (ASC). Preliminary results shown here demonstrate that TGFj3 is the first physiologically relevant growth factor that perturbs lens cell gap junctions in an manner dependent on the concentration of FGF. The goals of the proposed studies are: (1) To define the signaling mechanisms whereby TGFj3 perturbs gap junction-mediated intercellular communication between lens cells, and (2) To elucidate the in vivo role of BMP4 in secondary fiber differentiation in transgenic mice. This abstract was revised to match the two year length of this award.