Regulation of Lens Cell Coupling and Differentiation

据估计，有2050万美国人患有白内障。在之前的研究中，我们开发了一种无血清的原代胚鸡晶状体细胞培养系统（DCDMLs），并使用它来证明，在体内晶状体赤道可用的水平下，成纤维细胞生长因子（FGF）上调间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FGF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。对晶状体中过表达BMP抑制剂的转基因小鼠的研究支持了正常晶状体发育和功能同时需要FGF和BMP信号通路的假设。另一种眼部生长因子TGFj3参与了前囊下白内障（ASC）的发展。本研究的初步结果表明，TGFj3是第一个以依赖于FGF浓度的方式干扰晶状体细胞间隙连接的生理相关生长因子。本研究的目的是：(1)明确TGFj3干扰晶状体细胞间隙连接介导的细胞间通讯的信号机制；(2)阐明BMP4在转基因小鼠体内对次生纤维分化的作用。

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.