The lens capsule is a thickened basement membrane surrounding the lens which provides essential structural support for lens cells and mediates connection between the lens and the remainder of the eye. Lens capsule components also serve as survival, proliferation and differentiation signals for the attached lens cells although te relative contribution of each extracellular matrix protein found in the lens capsule to lens cell behavior is mostly uncharacterized. Integrins are major molecules mediating the communication between cells and their extracellular matrix. During the prior grant cycle we discovered that various integrins play essential roles in lens development as well as the pathogenesis of posterior capsular opacification (PCO), the major side effect of surgical cataract removal. However, the mechanisms by which integrins control lens development and the pathogenesis of PCO is not well understood. This application proposes to investigate the molecular mechanisms by which integrins control the fate decisions which regulate transitions from lens epithelial cells to fiber cells during development and "pearl type" PCO as well as transitions between epithelial cells and myofibroblasts during the process of fibrotic PCO development. These studies include investigations into the molecular function of fibronectin, an integrin ligand known to upregulate during PCO, in the pathogenesis of this condition.

Public Health Relevance

The lens capsule is an understudied, but crucial regulator of lens biology. This application seeks to understand the molecular mechanisms underlying its fundamental role in both the regulation of normal lens biology and the conversion of lens epithelial cells to myofibroblasts, a main component of scar tissue. This work will provide fundamental insights into the pathogenesis of after-cataract (posterior capsular opacification), the major side effect of cataract surgery. This will allow us to identify additional molecular targets to prevent this condition which could result in better final visual outcomes for patients.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY015279-09
Application #
8399302
Study Section
Special Emphasis Panel (BVS)
Program Officer
Araj, Houmam H
Project Start
2003-12-01
Project End
2014-09-29
Budget Start
2012-09-30
Budget End
2014-09-29
Support Year
9
Fiscal Year
2012
Total Cost
$382,500
Indirect Cost
$132,500
Name
University of Delaware
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
Lyu, Lei; Whitcomb, Elizabeth A; Jiang, Shuhong et al. (2016) Unfolded-protein response-associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract. FASEB J 30:1087-95
Sadaka, Ama; Sisk, Robert A; Osher, James M et al. (2016) Intravitreal methotrexate infusion for proliferative vitreoretinopathy. Clin Ophthalmol 10:1811-1817
Audette, Dylan S; Scheiblin, David A; Duncan, Melinda K (2016) The molecular mechanisms underlying lens fiber elongation. Exp Eye Res :
Pathania, Mallika; Wang, Yan; Simirskii, Vladimir N et al. (2016) β1-integrin controls cell fate specification in early lens development. Differentiation 92:133-147
Mamuya, Fahmy A; Wang, Yan; Roop, Victoria H et al. (2014) The roles of αV integrins in lens EMT and posterior capsular opacification. J Cell Mol Med 18:656-70
Pathania, Mallika; Semina, Elena V; Duncan, Melinda K (2014) Lens extrusion from Laminin alpha 1 mutant zebrafish. ScientificWorldJournal 2014:524929
Scheiblin, David A; Gao, Junyuan; Caplan, Jeffrey L et al. (2014) Beta-1 integrin is important for the structural maintenance and homeostasis of differentiating fiber cells. Int J Biochem Cell Biol 50:132-45
Simirskii, V N; Duncan, M K; Paltsev, M A et al. (2013) β1 integrin as the integrating component in cell-cell cooperation for maintenance of lens transparency. Dokl Biochem Biophys 453:297-9
Mamuya, Fahmy A; Duncan, Melinda K (2012) aV integrins and TGF-β-induced EMT: a circle of regulation. J Cell Mol Med 16:445-55
Alapure, Bhagwat V; Stull, Jaime K; Firtina, Zeynep et al. (2012) The unfolded protein response is activated in connexin 50 mutant mouse lenses. Exp Eye Res 102:28-37

Showing the most recent 10 out of 25 publications