The long-term goals of this application are to examine how a6 integrin signaling pathways regulate lens cell differentiation and to determine how changes in this integrin signaling pathway may mediate cell migration that leads to posterior capsule opacification (PCO) following cataract surgery. During the last funding period we demonstrated that a6 integrin is required for lens cell differentiation. We then began our investigation of potential a6 integrin signaling pathways in the developing lens, focusing on the relationship between a6 integrin and growth factor signaling. We have discovered that the insulin-like growth factor-1 receptor (IGF-1R) becomes associated with a6 integrin during lens cell differentiation and that the IGF-1R in this a6 integrin signaling complex is tyrosine phosphorylated. We determined that other molecules known to be downstream of the IGF-1R signaling pathway, Shc and extracellular signal-regulated kinase (ERK), were also associated with a6 integrin in the embryonic lens. These investigations led us to examine potential regulators of a6 integrin/IGF-IR signaling in the lens. A role was identified for the Src family kinases (SFKs) in regulation of both lens cell proliferation and differentiation. We have made significant advances in determining the requisite role for a6 integrin in lens cell differentiation and defining the components of the a6 integrin signaling complex. This continuation application is focused on mapping a6 integrin signaling pathways and determining how they are regulated in order to understand a6 integrin function in mediating lens cell differentiation. We propose an integrated approach to map the signaling pathways including genetic, biochemical and cell biological studies. a6 integrin, through its association with different signaling pathways, also could play role a role in mediating the migration of lens epithelial cells along the posterior capsule as occurs in PCO following cataract surgery. We will use a model for PCO to investigate whether changes in a6 integrin signaling mediate cell migration in PCO. We will also investigate possible therapies to block integrin-mediated cell migration in PCO.
The specific aims are: 1) Investigate the hypothesis that the activation of a6 integrin induces a signaling pathway involving activation of IGF-1R and its downstream signaling effectors; 2) Examine the hypothesis that Src family kinases play a central role in lens cell differentiation through their regulation of a6 integrin/IGF-1R coordinated signaling; and 3) Examine the hypothesis that PCO is triggered by changes in a6 integrin/IGF-1R signaling which lead to the acquisition of a migratory phenotype by lens epithelial cells. These studies also will examine whether inhibition of SFKS could prevent PCO.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010577-10
Application #
6624441
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Liberman, Ellen S
Project Start
1993-08-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
10
Fiscal Year
2003
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
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Basu, Subhasree; Rajakaruna, Suren; De Arcangelis, Adèle et al. (2014) ?6 integrin transactivates insulin-like growth factor receptor-1 (IGF-1R) to regulate caspase-3-mediated lens epithelial cell differentiation initiation. J Biol Chem 289:3842-55
Basu, Subhasree; Rajakaruna, Suren; Dickinson, Bryan C et al. (2014) Endogenous hydrogen peroxide production in the epithelium of the developing embryonic lens. Mol Vis 20:458-67
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
Chauss, Daniel; Basu, Subhasree; Rajakaruna, Suren et al. (2014) Differentiation state-specific mitochondrial dynamic regulatory networks are revealed by global transcriptional analysis of the developing chicken lens. G3 (Bethesda) 4:1515-27
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
Costello, M Joseph; Brennan, Lisa A; Basu, Subharsee et al. (2013) Autophagy and mitophagy participate in ocular lens organelle degradation. Exp Eye Res 116:141-50
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 28 publications