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.
Cataracts are the leading cause of blindness world-wide, and are responsible for ~60% of all vision-related Medicare expenditures. The goal of this research is to understand how two processes required for lens transparency, gap junction-mediated intercellular communication and formation of crystallin-rich lens fiber cells, are regulated, and how they are disrupted by cataract-associated changes in growth factor signaling and/or mutation. This information will help develop therapies to combat the vision-destroying effects of cataract and of the most common complication of cataract surgery, posterior capsule opacification.
