Activation of Src tyrosine kinases occurs in response to oxidative, heat, and UV stress, all stress stimuli that promote the formation of lens cataract. We have found that inhibition of Src family tyrosine kinases (SFKs) blocks the development of lens opacity. In this proposal we will identify the molecular mechanisms by which SFK activation induces cataract formation. Our long term objectives are to identify the alterations in signaling pathways that lead to lens disease. The signaling intermediates in these networks are likely candidates for pharmaceutical intervention to suppress the formation of lens opacities. Key to understanding how the activation of SFKs leads to cataract formation is the delineation of SFK functions in normal lens differentiation and development. We will determine the mechanisms whereby SFKs regulate cadherin function in the developing embryonic lens. To extend these studies to the pathophysiology of lens cataract, we will examine the structural and functional targets of inappropriately activation of SFKs, focusing on cadherin junction destabilization, using two Src-induced lens disease models. One is an in vitro model in which lens cell cultures are transformed with a temperature sensitive v-Src kinase with which we will dissect the molecular affects of Src activation on the stabilization and function of lens cadherin junctions at different stages of development. These studies will be paralleled in a whole lens culture model that closely approximates stress-induced cataract. In this model we will be able to link the molecular changes that result from the inappropriate activation of SFKs with the formation of lens opacities. We hypothesize that one mechanism by which SFKs influence lens cell differentiation is through their regulation of cadherin complexes and that inappropriate regulation of the SFK signaling pathways induces lens cataracts by destabilizing cadherin junctions. We propose to 1) determine the mechanisms whereby Src family kinases regulate cadherin function in normal lens cell differentiation; 2) determine the mechanisms whereby constitutive activation of the Src kinase interferes with the structure and function of lens cadherin junctions, using v-Src transformed lens cell cultures as a model for stress-induced lens disease; and 3) determine the mechanisms whereby the inappropriate activation of Src family kinases, through their targeting of cadherin junctions, induces formation of lens cataracts.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014258-02
Application #
6754439
Study Section
Special Emphasis Panel (ZRG1-VISA (01))
Program Officer
Liberman, Ellen S
Project Start
2003-06-02
Project End
2007-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$353,250
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Logan, Caitlin M; Bowen, Caitlin J; Menko, A Sue (2018) Functional role for stable microtubules in lens fiber cell elongation. Exp Cell Res 362:477-488
Logan, Caitlin M; Rajakaruna, Suren; Bowen, Caitlin et al. (2017) N-cadherin regulates signaling mechanisms required for lens fiber cell elongation and lens morphogenesis. Dev Biol 428:118-134
Logan, Caitlin M; Bowen, Caitlin J; Menko, A Sue (2017) Induction of Immune Surveillance of the Dysmorphogenic Lens. Sci Rep 7:16235
Basu, Subhasree; Rajakaruna, Suren; Reyes, Beverly et al. (2014) Suppression of MAPK/JNK-MTORC1 signaling leads to premature loss of organelles and nuclei by autophagy during terminal differentiation of lens fiber cells. Autophagy 10:1193-211
Menko, A S; Bleaken, B M; Libowitz, A A et al. (2014) A central role for vimentin in regulating repair function during healing of the lens epithelium. Mol Biol Cell 25:776-90
Menko, A S; Bleaken, B M; Walker, J L (2014) Regional-specific alterations in cell-cell junctions, cytoskeletal networks and myosin-mediated mechanical cues coordinate collectivity of movement of epithelial cells in response to injury. Exp Cell Res 322:133-48
Leonard, Michelle; Zhang, Liping; Bleaken, Brigid M et al. (2013) Distinct roles for N-Cadherin linked c-Src and fyn kinases in lens development. Dev Dyn 242:469-84
Basu, Subhasree; Rajakaruna, Suren; Menko, A Sue (2012) Insulin-like growth factor receptor-1 and nuclear factor ?B are crucial survival signals that regulate caspase-3-mediated lens epithelial cell differentiation initiation. J Biol Chem 287:8384-97
Leonard, Michelle; Zhang, Liping; Zhai, Ni et al. (2011) Modulation of N-cadherin junctions and their role as epicenters of differentiation-specific actin regulation in the developing lens. Dev Biol 349:363-77
Menko, A Sue; Andley, Usha P (2010) ?A-Crystallin associates with ?6 integrin receptor complexes and regulates cellular signaling. Exp Eye Res 91:640-51

Showing the most recent 10 out of 19 publications