Ras & PI 3-Kinase Signaling in Lens Development

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DESCRIPTION (provided by applicant): Lens cell proliferation and differentiation are precisely regulated to achieve the normal structures of the lens. It is believed that the growth factors present in the ocular media control lens growth and development. Presently, we know very little about the growth factor signaling events in lens development. In most cell types, a growth factor binding its receptor will trigger the receptor tyrosine kinase activity which activates Ras, a small GTP-binding protein. Ras functions as a relay switch by transmitting the upstream signal to the various downstream effectors. Our overall hypothesis is that Ras and its downstream effectors, Raf kinase and phosphoinositide 3-kinase (PI 3-kinase), play important roles during lens development. Therefore, I propose the following specific aims: 1) Test whether the Ras/Raf/MEK (MAP Erk kinase)/Erk (extracellular ligand regulated kinase) pathway controls lens cell proliferation. 2) Determine the role of PI 3-kinase and its downstream target Akt/protein kinase B (PKB) in lens cell survival. 3) Determine the role of PI 3-kinase in regulating cell size and morphology during fiber cell differentiation. 4) Characterize the downstream signaling events of insulin receptor substrate-1 (IRS-1) activation in transgenic lens. The experiments proposed in this grant application can not only provide us new information on the signaling mechanisms present during lens development, but can also establish an in vivo model to study signal transduction pathways in a developmental system. Successful development of inhibitors for lens epithelial cell proliferation and survival may provide an effective treatment or prevention of posterior capsule opacification (PCO) (also called "after-cataract").