The lens capsule is a thickened basement membrane that completely surrounds the lens from its earliest developmental stages until death. It is well established that the lens capsule is crucial for lens development and function and lens capsule pathologies can threaten vision. An established function of the lens capsule is to serve as a selectable filter between the lens and the ocular environment, however, relatively little is known about the properties of this filter. During the prior grant cycle, we developed a robust fluorescence recovery after photobleaching (FRAP) protocol which can evaluate both the ability of molecules to enter the lens capsule and quantitatively determine their diffusion coefficient. In the first aim of this application, we propose to use FRAP to elucidate the molecular properties of the normal lens capsule filter. It is also known that mutations in extracellular matrix (ECM) protein genes result in cataract.
The second aim tests the hypothesis that alterations in collagen IV activate the unfolded protein response leading to cataract. Another established function of the lens capsule is to engage ECM receptors on lens cells, providing both a structural anchor for the cell and inducing cell signaling cascades crucial for lens cell phenotype. Integrins are a major class of ECM receptors present on lens cells and (31 integrin is the major p-integrin subunit expressed by the lens. In the prior grant cycle, we created mice lacking pi integrin in either all lens cells or just lens fibers to test the hypothesis that pi -integrin is important for lens cell/lens capsule communication. The phenotypes of the resulting animals are quite distinct and we now propose in specific aim three to elucidate the function of pi-integrin in the in vivo lens by analyzing the molecular abnormalities seen in these animals. Public Health Relevance: The lens capsule is important for the function of the normal ocular lens, although little is known about how diseases affecting the lens capsule result in lens abnormalities. Further, the lens capsule is usually retained in the eye after the surgical removal of cataracts to both support the implanted artificial replacement lens and to serve as a barrier,between the anterior and posterior portions of the eye, although the resulting abnormal lens cell/capsule interactions often result in secondary cataract. A complete understanding of the communication between lens cells and the capsule are crucial to develop treatments to prevent secondary cataract.
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| Audette, Dylan S; Scheiblin, David A; Duncan, Melinda K (2017) The molecular mechanisms underlying lens fiber elongation. Exp Eye Res 156:41-49 |
| Wang, Yichen; Terrell, Anne M; Riggio, Brittany A et al. (2017) ?1-Integrin Deletion From the Lens Activates Cellular Stress Responses Leading to Apoptosis and Fibrosis. Invest Ophthalmol Vis Sci 58:3896-3922 |
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| 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 |
| Pathania, Mallika; Wang, Yan; Simirskii, Vladimir N et al. (2016) ?1-integrin controls cell fate specification in early lens development. Differentiation 92:133-147 |
| 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 |
| Mamuya, Fahmy A; Wang, Yan; Roop, Victoria H et al. (2014) The roles of ?V 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 |
| Simirskii, V N; Duncan, M K; Paltsev, M A et al. (2013) ?1 integrin as the integrating component in cell-cell cooperation for maintenance of lens transparency. Dokl Biochem Biophys 453:297-9 |
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