Regulation of Lens Cell Coupling and Differentiation

据估计，有2050万美国人患有白内障。在以前的研究中，我们建立了无血清原代胚胎鸡晶状体细胞培养系统(DCDMLs)，并利用它表明，体内晶状体赤道水平的成纤维细胞生长因子(成纤维生长因子)上调了缝隙连接介导的细胞间通讯和上皮-纤维分化标志物的表达。最近，我们已经证明了成纤维细胞生长因子促进这些过程的能力完全依赖于晶状体来源的骨形态发生蛋白(BMP)-4和/或7。在转基因小鼠晶状体中过度表达BMP抑制物的研究支持这样的假设，即正常的晶状体发育和功能同时需要成纤维细胞生长因子和骨形态发生蛋白信号通路。另一种眼生长因子TGFj3与前囊下白内障(ASC)的发生有关。初步结果表明，TGFj3是第一个与生理相关的生长因子，它以一种依赖于成纤维细胞生长因子浓度的方式干扰晶状体细胞缝隙连接。本研究的目的是：(1)明确TGFj3干扰缝隙连接介导的晶状体细胞间通讯的信号机制；(2)在体内阐明BMP4在转基因小鼠次级纤维分化中的作用。 这份摘要经过了修改，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.