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"""""""").

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013146-04
Application #
6782670
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Liberman, Ellen S
Project Start
2001-08-01
Project End
2007-11-30
Budget Start
2004-08-01
Budget End
2007-11-30
Support Year
4
Fiscal Year
2004
Total Cost
$253,750
Indirect Cost
Name
University of Missouri-Columbia
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
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Zhang, Jinglin; Upadhya, Dinesh; Lu, Lin et al. (2015) Fibroblast growth factor receptor 2 (FGFR2) is required for corneal epithelial cell proliferation and differentiation during embryonic development. PLoS One 10:e0117089
Upadhya, Dinesh; Ogata, Masato; Reneker, Lixing W (2013) MAPK1 is required for establishing the pattern of cell proliferation and for cell survival during lens development. Development 140:1573-82
Reneker, Lixing W; Chen, Huiyi; Overbeek, Paul A (2011) Activation of unfolded protein response in transgenic mouse lenses. Invest Ophthalmol Vis Sci 52:2100-8
Newitt, Peter; Boros, Jessica; Madakashira, Bhavani P et al. (2010) Sef is a negative regulator of fiber cell differentiation in the ocular lens. Differentiation 80:53-67
Reneker, Lixing W; Bloch, Amy; Xie, Leike et al. (2010) Induction of corneal myofibroblasts by lens-derived transforming growth factor beta1 (TGFbeta1): a transgenic mouse model. Brain Res Bull 81:287-96
Maddala, Rupalatha; Reneker, Lixing W; Pendurthi, Bhavana et al. (2008) Rho GDP dissociation inhibitor-mediated disruption of Rho GTPase activity impairs lens fiber cell migration, elongation and survival. Dev Biol 315:217-31
Xie, Leike; Chen, Huiyi; Overbeek, Paul A et al. (2007) Elevated insulin signaling disrupts the growth and differentiation pattern of the mouse lens. Mol Vis 13:397-407
Fan, Xingjun; Reneker, Lixing W; Obrenovich, Mark E et al. (2006) Vitamin C mediates chemical aging of lens crystallins by the Maillard reaction in a humanized mouse model. Proc Natl Acad Sci U S A 103:16912-7
Xie, Leike; Overbeek, Paul A; Reneker, Lixing W (2006) Ras signaling is essential for lens cell proliferation and lens growth during development. Dev Biol 298:403-14

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